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Abstract

Objective/Background

Natural products (NPs) derived from microorganisms are the basis of a plethora of clinically utilized medications, namely, antimicrobial remedies. Although these secondary metabolites have been extensively explored all over the planet, they remain understudied in the Middle East and North Africa (MENA) region.

Methods

A literature search was conducted to first find NPs that were isolated from environmental fungi and bacteria that inhabit the soils and seawater of the MENA region. Then, purified molecules with biological activity against pathogenic bacteria, biofilms, fungi, and parasites were described in terms of structure, function, and location. Moreover, the methods that could be used to ameliorate the discovery of novel NPs from this region were investigated.

Results

A multitude of antimicrobial molecules from various chemical classes were found to be derived from the environmental microbes of MENA. Although many were rediscovered, some represented novel structural scaffolds for novel families of antimicrobial agents. Additionally, the geographical distribution showed a high number of these NPs were unraveled in a restricted area leaving much of MENA untapped. Furthermore, as relatively traditional and low-efficiency methods were typically used in the discovery process, advanced high-throughput techniques were suggested to enhance this practice at the regional level.

Conclusion

MENA represents a fairly unexploited region where antimicrobial drug discovery could be performed comprehensively through the concomitant exploration of untouched geographical locations and advanced molecular techniques.

Keywords

quinones alkaloids peptides polyketides coumarins MENA antimicrobial

Introduction

Antimicrobial resistance (AMR) is a phenomenon where microorganisms progressively change and become non-responsive to drugs originally designed to kill them.^1,2 The term AMR is interchangeably used to describe the resistance of bacteria to their antimicrobials. Nonetheless, it can be also applied to the decreased susceptibility that other microbes (viruses, fungi, and parasites) might display against their antimicrobial agents.³ The different forms of AMR pose an issue all over the planet. For example, in the United States, more than 2.8 million people are infected by antibiotic-resistant bacteria yearly, of whom 35 000 individuals pass away.⁴ On the other hand, in malaria-endemic countries, the spread of artemisinin-resistant strains is predicted to add 116 000 deaths to the annual count of more than 400 000.^5‐7 Moreover, the global burden of AMR is suspected to increase, becoming the leading cause of death by 2050 with more than 10 million casualties being associated with antimicrobial-resistant infections each year.^8,9 Furthermore, the overwhelming financial load of AMR is even more destructive with estimations that AMR-associated costs could surpass 1 trillion dollars per annum by 2050.¹⁰

Treating infections caused by drug-resistant pathogens requires switching from one class of antimicrobial to the other. However, the emergence of multidrug-resistant (MDR), extensively drug-resistant, and pandrug-resistant (PDR) microorganisms with resistance to all classes of antimicrobials has rendered this strategy useless.^11‐13 Alternatively, two main approaches arise, either the usage of combination therapy of different antimicrobials or the discovery of new classes of antimicrobial agents.^14,15 The former is already showing significant inhibitions of the growth of pathogens in clinical settings.^14,16,17 Nevertheless, long-term exposure to the antimicrobials used in these combinations can eventually induce resistance to these mixtures in vitro and in vivo.^18‐22 Henceforth, the discovery journey must be the path to take, to ensure victory against PDR pathogens. Researchers can choose between multiple tactics to find a hit drug against superbugs: in silico screening/molecular docking, fragment and structure-based approaches, hybrid inhibitor design, drug repurposing, and exploring natural products (NPs).²³ Although the last appears the most primitive in concept, it has shown time after time to be essential in drug discovery. This could be seen by the fact that NPs, their derivatives, and their mimics represent around 50% of all approved drugs between 1981 and 2019. They also exemplify approximately 50% of all antimicrobial drugs discovered in that period.²⁴ Additionally, the return to the inspection of NPs for antimicrobial biological activities is further reinforced by the relative ineffectiveness of molecular and biochemical approaches. These techniques were unable to yield the expected increase in the number of newly discovered classes of anti-infective agents although they have been utilized in this type of research for several decades.²⁵

NPs are secondary metabolites (SMs) that originate from a variety of organisms such as plants, terrestrial and marine microorganisms, invertebrates, and less frequently vertebrates.²⁶ Those derived from microorganisms have shown great potential in antimicrobial drug discovery.^27‐29 However, since research in the past has been limited to a narrow range of microbial NP producers, the chances of novel drug discovery have been relatively low.^{30, 31} Consequently, the search for untapped genera and species has been deemed worthy, especially in highly biodiverse areas.^32‐34 The main path to finding these understudied microbes might be in targeting fairly unexploited regions where these untouched bugs might be thriving. The Middle East and North Africa (MENA) region is characterized by its immense biodiversity while being relatively untapped when it comes to drug discovery. Thus, in this review, we will be focusing on antimicrobial agents derived from microorganisms inhabiting the MENA region (Mauritania, Morocco, Algeria, Tunisia, Libya, Egypt, Sudan, Palestine, Jordan, Lebanon, Syria, Saudi Arabia, Yemen, Oman, United Arab Emirates, Qatar, Bahrain, Kuwait, Iraq, and Iran). We will also be describing their actions on various pathogens with indication of quantitative parameters when available. Moreover, we will be shedding light on their cytotoxic activity when applicable. Finally, we will be discussing the methods that can be used to enhance the opportunities of their discovery.

Pure Compounds

In the following section, we will be describing completely purified antimicrobial NPs isolated from fungi and bacteria found in the MENA region, residing in both terrestrial and marine niches.

Fungi

An unexpected number of chemically diverse SMs exhibiting antimicrobial activities emerged from marine fungi living in the MENA region, as shown in Table 1. Starting from the Red Sea, an inlet of the Indian Ocean, lying between Africa and Asia, where ditryptophenaline (Structure 1) was discovered at the coast of Ein El-Sukhna-Zafarana, Egypt. This compound was isolated from Aspergillus ochraceopetaliformis MN0-83316, a symbiote of the coral Galaxea fascicuralis and was previously isolated from Aspergillus flavus.³⁵ This diketopiperazine homodimer consists of two identical halves, each of which possesses 4 fused rings including an indoline function cis fused to a pyrrolidine ring and a fully substituted 2,5-dioxopiperazine ring with a benzyl at C5 and a methyl at N6. Ditryptophenaline demonstrated antimicrobial activity against Gram-positive (Bacillus subtilis subsp. spizizenii ATCC 6633) and Gram-negative (Escherichia coli ATCC 11775) bacteria, as well as against the fungus Candida parapsilosis ATCC 22019. The inhibition zones ranged from 8 to 9 mm when the compound concentration was set at 50 mmoles.³⁶

Table 1.

Compounds Derived from Fungi Inhabiting the MENA Region.

Compound	Class	Producer	Mode of action	Location	Ref.
Ditryptophenaline	Diketopiperazine	Aspergillus ochraceopetaliformis MN0-83316, symbiont of the coral Galaxea fascicularis	Antibacterial activity against E. coli, B. subtilis Antifungal activity against Candida. parapsilosis	Red Sea, coast of Ein El-Sukhna-Zafarana, Egypt	³⁶
Isorhodoptilometrin-1-methyl ether	Quinone	Aspergillus versicolor inhabiting the green alga Halimeda opuntia	Antibacterial activity against B. subtilis, B. cereus and S. aureus	Red Sea, coast of Rass Mohamed, Egypt	³⁷
Siderin	Benzopyrone			Red Sea, coast of Rass Mohamed, Egypt	³⁷
w-Hydroxyemodin	Quinone	Fusarium equiseti inhabiting the brown alga Padina pavonica	Antibacterial activity against S. aureus, Bacillus megaterium, and B. subtilis Antifungal activity against C. albicans	Red Sea, coast of South Hurghada, Egypt	³⁸
Cordycepin	Nucleoside
17-Demethyl-2,11-dideoxy- rhizoxin	Macrolide		Antibacterial activity against S. aureus and Bacillus megaterium Antifungal activity against C. albicans
Brevianamide F	Diketopiperazine	Penicillium vinaceum inhabiting the sponge Hyrtios erectus	Antibacterial activity against S. aureus Antifungal activity against C. albicans	Red Sea, coast of Yanbu, Saudi Arabia	³⁹
Citreoisocoumarin	Benzopyrone		Antibacterial activity against S. aureus
Iso-α-cyclopiazonic acid	Alkaloid		Antibacterial activity against E. coli
Terretrione A	Benzodiazepine		Antifungal activity against C. albicans
Terretriones C (11) and D (12)	Benzodiazepine	Penicillium sp. CYE-87 inhabiting the tunicate Didemnum sp.	Antifungal activity against C. albicans	Suez Canal, Egypt	⁴⁰
Penicilloitin A	Fatty acid ester	Penicillium sp. inhabiting the tunicate Didemnum sp.	Antibacterial activity against E. coli	Red sea, mangrove forest, Sharm El-Sheikh, Egypt	⁴¹
α-Cyclopiazonic acid (14) and tryptamine (15)	Alkaloid		Antibacterial activity against E. coli
Penicilloitin B	Fatty acid ester		Antibacterial activity against E. coli and S. aureus
Dibutyl phthalate	Phthalate	Varicosporina ramulosa inhabiting algae	Antibacterial activity against E. coli and B. subtilis Antifungal activity against C. albicans and Fusarium. solani	Mediterranean Sea, coast of Abou-Keer, Alexandria, Egypt	⁴²
Ergosta-5,7,22-trien-3β-ol	Ergosterol	Varicosporina ramulosa inhabiting algae	Antibacterial activity against E. coli and B. subtilis Antifungal activity against C. albicans	Mediterranean Sea, coast of Abou-Keer, Alexandria, Egypt	⁴²
Trichorzianines: TA 1938 (19), 1909, 1895, 1896, 1924, 1910, 1924a, 1909a, VIb, VIa, Vb	Peptides	Trichoderma atroviride NF16 inhabiting an Axinellid sponge	Antibacterial activity against environmental bacteria Bacillus sp. NB36, Sporosarcina sp. NB90, Microbacterium sp. PII.14, Shewanella sp. PIII.07, and Rhodobacteraceae PI.03 Modest antibacterial activity against B. subtilis and Staphylococcus albus	Mediterr-anean Sea, coast of Akhziv, Israel	⁴³
Insuetolide A	Terpenoid	Aspergillus insuetus OY-207 inhabiting the sponge Psammocinia sp.	Antifungal activity against Neurospora crassa	Mediterr-anean Sea, offshore Sdot-Yam, Israel	⁴⁴
Strobilactone A (21) and (E,E)-6-(60,70- dihydroxy-20,40-octadienoyl)-Strobilactone A	Terpenes				⁴⁴
2-Carboxymethyl-3-hexylmaleic acid anhydride	Anhydride	Aspergillus tubingensis OY907 inhabiting the sponge Ircinia variabilis			⁴⁵
Tubingenoic anhydride A	Anhydride		Antifungal activity against Neurospora crassa mediated by the MAS1 Protein		⁴⁵
Trans-2-octenal	Aldehyde	Daldinia cf concentrica, an endophyte of the olive tree Olea europaea	Antifungal activity against Aspergillus niger, Botrytis cinerea, Alternaria alternata, and Penicillium digitatum	Ha'Ela Valley, Judean Hills, Israel	⁴⁶
4-Heptanone	Ketone		Antifungal activity against Botrytis cinerea	Ha'Ela Valley, Judean Hills, Israel	⁴⁶
Preussilides A (26) and C (27)	Bicyclic Polyketide	Preussia similis DSM 104666 inhabiting the medicinal plant Globularia alypum	Antifungal activity against Aspergillus fumigatus, Mucorscle plumbeus, and Sclerotinia sclerotiorum	Batna, Algeria	⁴⁷

Abbreviation: MENA, Middle East and North Africa.

The Egyptian Red Sea is also the home to Halimeda opuntia, which was collected from the coast of Rass Mohamed, Egypt. This green alga shelters the fungus Aspergillus versicolor, which synthesizes several bioactive compounds. One instance is the previously isolated Siderin (Structure 3),⁴⁸ a coumarin derivative benzopyrone with 2 methoxy groups at C4 and C7, as well as a methyl at C5 that was formerly purified from the plant Toona ciliata. Another example is the novel tricyclic anthraquinone Isorhodoptilometrin-1-methyl ether (Structure 2), with a methoxy group at C1, hydroxy groups at C6, and C8, as well as a 2-hydroxypropyl attached at C3. Both of these compounds demonstrated antibacterial activity against Gram-positive pathogens B. subtilis, Bacillus cereus, and Staphylococcus aureus with zones of inhibition ranging between 11 and 15 mm. Thus, both these molecules were less potent than the control drug, Oxytetracycline, whose zones of inhibition against these pathogens ranged from 17 to 20 mm. Moreover, these compounds showed null to minimal cytotoxicity against the normal human cell line CFU-GM.³⁷

Another endophytic fungus of an alga was found off the coast of South Hurghada, Egypt. It was classified as Fusarium equiseti. This fungus inhabits the brown alga Padina pavonica and has shown the ability to secrete an abundance of previously discovered NPs. Examples comprise the nucleoside Cordycepin (3’-deoxyadenosine, Structure 5), originating from Cordyceps militari,⁴⁹ the macrolide 17-demethyl-2,11-dideoxy-rhizoxin (Structure 6), with a tetraoxatetracyclohenicos-14-ene-6,19-dione, which was first isolated from a Rhizopus species,⁵⁰ and w-Hydroxyemodin (Structure 4), a tricyclic anthraquinone with hydroxy groups at C1, C3, and C8, as well as a hydroxymethyl group at C6, known to be a constituent of Penicillium chrysogenum.⁵¹ All of these compounds exhibited antifungal activity against the fungus Candida albicans (C. albicans). Moreover, they demonstrated antibacterial activity against S. aureus and Bacillus megaterium, while Cordycepin and w-Hydroxyemodin also inhibited the growth of B. subtilis. Besides, their potency against these bacterial pathogens was either inferior or equal to that of the control drug Oxytetracycline.³⁸

Red Sea marine fungi whose SMs proved to possess antimicrobial potential were also found in sponges. Hyrtios erectus found off the coast of the Saudi Arabian city of Yanbu houses Penicillium vinaceum. This fungus yielded a plethora of antimicrobial NPs such as the diketopiperazine derivative Brevianamide F (Structure 7), a hexahydropyrrolo[1,2-a]pyrazine-1,4-dione with an indol-3-ylmethyl substituent at position 3, which was previously isolated from Aspergillus fumigatus.⁵² Another compound is Citreoisocoumarin (Structure 8), a coumarin derivative with hydroxy groups at C6 and C8, as well as 2-hydroxy-4-oxopentyl attached at C3, previously purified from a culture of Penicillium nalgiovense.⁵³ Both these molecules inhibited the growth of S. aureus ATCC 25923 with a 19-mm inhibition zone. The fungal culture also generated iso-α-cyclopiazonic acid (Structure 9); an ergoline derivative alkaloid previously obtained from A. flavus.⁵⁴ It showed the ability to inhibit the growth of E. coli ATCC 25922 with a 20-mm zone. Moreover, the researchers detected the known metabolite Terretrione A (Structure 10), previously found in a culture of Aspergillus terreus.⁵⁵ This compound possesses a 1,4-diazepane core structure demethylated at positions 1 and 4, with carbonyl groups at C2, C5, and C7 as well as benzyl at C6 and 2-methylpropyl at C3. Terretrione A, alongside Brevianamide F, inhibited the growth of C. albicans ATCC 14053 with a 25-27 mm inhibition zone. All the aforementioned NPs were less potent against these bacterial and fungal pathogens than their respective reference drugs: ampicillin, imipenem, and clotrimazole.³⁹

Similarly, other Terretriones were discovered from Penicillium sp. CYE-87 inhabiting the tunicate Didemnum sp. from the Suez Canal, Egypt. They included the previously isolated Terretrione C (Structure 11)⁵⁵ and the newly deciphered Terretrione D (Structure 12). They both resemble Terretrione A; however, C has a butan-2-yl at C3, while D lacks a methyl group at position 4 and has a propan-2-yl at C3. Both of these NPs exhibited antifungal activity against C. albicans ATCC 14053 with inhibition zones of 17-19 mm. Their minimal inhibitory concentration (MIC) was determined to be 32 μg/mL against the same strain.⁴⁰ Another Penicillium species inhabiting a tunicate of the Didemnum genus was isolated from the Egyptian Red Sea from a mangrove forest at Sharm El-Sheikh. This microorganism generated 2 novel fatty acid esters Penicilloitins A (Structure 13) and B (Structure 16). Additionally, it generated known alkaloids: the ergoline derivative α-cyclopiazonic acid (Structure 14),⁵⁴ and the indolamine tryptamine (Structure 15). All of these compounds inhibited the growth of E. coli ATCC 25922 with zones of 20-22 mm, while only Penicilloitin B inhibited S. aureus ATCC 25923 with a 19-mm zone. These SMs were less efficient in inhibiting the growth of these pathogens when compared to the reference drugs imipenem and ampicillin.⁴¹

The fungi of the Mediterranean Sea also offer a rich source for the discovery of NPs. For example, Varicosporina ramulosa recovered from the coast of Abou-Keer, Alexandria, Egypt, generated 2 novel antimicrobial compounds. Dibutyl phthalate (Structure 17), a 1,2-diester of phthalic acid with 2 butan-1-ol, and, ergosta-5,7,22-trien-3β-ol, an ergosterol (Structure 18) related molecule. Both of these molecules inhibited the growth of E. coli, B. subtilis, and C. albicans, while only dibutyl phthalate inhibited the growth of Fusarium solani.⁴² Moreover, multiple novel Trichorzianines were isolated from Trichoderma atroviride NF16 coming from the coast of Akhziv. These peptaibols are linear non-ribosomal peptides (NRPs) with an acetylated N-terminus, C-terminal amino alcohol, and a high proportion of α-aminoisobutyric acid (Aib). The structure of one of them TA 1938 is shown in Table 1 (Structure 19). These peptides demonstrated a good antimicrobial activity on a range of environmental bacteria with MICs ranging between 12.5 and 200 μg/mL, while they only showed modest antibacterial activity on Staphylococcus albus and B. subtilis with MICs ranging between MIC 50 and 200 μg/mL.⁴³

Additionally, fungi inhabiting sponges collected offshore Sdot-Yam showed a diversity of chemical compounds with antifungal abilities. First, Aspergillus insuetus OY-207 inhabiting a sponge belonging to the genus Psammocinia synthesized the novel meroterpenoid Insuetolide A (Structure 20), possessing a tricos-8-ene-7,14,18-trione central structure, which inhibited the growth of the fungus Neurospora crassa with a MIC value of 140 μM. This fungus also gave rise to two drimane sesquiterpenes: Strobilactone A (Structure 21) and its derivative (E,E)-6-(60,70-dihydroxy-20,40-octadienoyl)-strobilactone A, previously isolated from Aspergillus and Strobilurus species.^56,57 They are characterized by a hexahydrobenzo-benzofuran-1-one and inhibited the growth of the fungus Neurospora crassa with MICs of 242 and 162 µM, respectively.⁴⁴ Second, Aspergillus tubingensis OY907 inhabiting the sponge Ircinia variabilis secreted the previously unexploited Tubingenoic anhydride A (Structure 23) and 2-carboxymethyl-3-hexylmaleic acid (Structure 22) anhydride, which was previously identified in cultures of Aspergillus FH-X-21.⁵⁸ Both these NPs inhibited the growth of Neurospora crassa with MICs of 330 and 207 μM, respectively.⁴⁵

Likewise, soil fungi demonstrated the ability to manufacture antimicrobial NPs, as seen for compounds originating from Daldinia cf concentrica, an endophyte of the olive tree Olea europaea, from Ha'Ela Valley, Judean Hills. These molecules include the antifungal aldehyde trans-2-octenal (Structure 24), previously isolated from O. europaea itself,⁵⁹ which inhibited the growth of the fungi Aspergillus niger, Botrytis cinerea, Alternaria alternata, and Penicillium digitatum. Additionally, this fungus secreted the antifungal ketone 4-heptanone (Structure 25), previously purified from Burkholderia ambifaria,⁶⁰ which inhibited the growth of B. cinerea.⁴⁶ Another example is noticed for the novel Preussilides A (Structure 26) and C (Structure 27), isolated from Preussia similis DSM 104666 inhabiting the medicinal plant Globularia alypum from Batna, Algeria. Preussilides are characterized by having a naphthalen-1-yl-4,6-dimethylhepta-24,6-trienoic acid core structure. These novel antifungal bicyclic polyketides showed activity against Mucor plumbeus (MIC 150 and 37.5 μg/mL) less efficiently than the control drug Nystatin (MIC 3.12 μg/mL). Preussilide C was also active against A. fumigatus DSM 819 (MIC 8.33 μg/mL), which was more effective than the control drug Cycloheximide (MIC 33.33 μg/mL) and Preussilide A (MIC 66.67 μg/mL). Moreover, both preussilides inhibited Sclerotinia sclerotiorum DSM 1946 with inhibition zones of 28 and 29 mm at 100 μg/paper disk. Both these compounds also exhibited moderate cytotoxicity against the normal mouse fibroblastic cell line L929, with IC50 values lower than 10 μM.⁴⁷

Bacteria

The profile of antimicrobial NPs purified from environmental bacteria was extensively diverse in respect to variation in both structure and function. The producing bacteria are spread out across the whole MENA region and inhabit both soil and water, as shown in Tables 2 and 3, respectively.

Table 2.

Compounds Derived from Soil bacteria Inhabiting the MENA Region.

Compound	Structure	Class	Producer	Mode of action	Location	Reference
3-Phenylpyrazin-2(1H)-one		Beznopyrazine	Streptomyces sp. TN82	Antibacterial activity against S. aureus, Listeria monocytogenes, and Salmonella typhimurium	Tunisian Saharan soil	⁶¹
3-O-Methylviridicatin		Quinolone	Streptomyces sp. TN82			⁶¹
N-[2-(1H-indol-3-yl)-2 oxo-ethyl] acetamide		Alkaloid	Streptomyces sp. TN256	Antibacterial activity against M. luteus, S. aureus, E. coli, and Salmonella enterica Antifungal activity against Fusarium sp.		⁶²
Di-(2-ethylhexyl) phthalate		Phthalate
1-Nonadecene		Alkene
Cyclo(L-Pro-L-Tyr)		Diketopiperazine
Cyclo(L-Leu-L-Pro)		Diketopiperazine	Streptomyces misionensis V16R3Y1	Broad-spectrum antibacterial and antifungal activity	Tunisian oasis soil	⁶³
Cineromycin B (35) and 2,3-Dihydrocineromycin B (36)		Macrolide	Streptomyces sp. TN262	Antibacterial activity against M. luteus and S. aureus	South Tunisian soil	⁶⁴
Tryptophol		Alcohol	Streptomyces sp. TN262	Antibacterial activity against M. luteus, S. aureus, and Salmonella enterica Antifungal activity against Fusarium sp.	South Tunisian soil	⁶⁴
Oligomycins A (38) and E (39)		Macrolide	Streptomyces sp. HG29	Antifungal activity against Aspergillus sp., Fusarium sp., Penicillium sp.	Algerian Saharan soil	⁶⁵
( − )-8-O-methyltetrangomycin (40) and ( − )-7-deoxy-8-O- methyltetrangomycin (41)		Angucyclinone	Nocardiopsis sp. HR-4	Antibacterial activity against S. aureus, M. luteus, and Enterococcus faecalis	Salt lake soil from Sebkha of Ain Salah of the Algerian Sahara Desert	⁶⁶
Meroparamycin			Streptomyces sp. MAR01	Antibacterial activity against M. luteus, B. subtilis, E. coli, S. aureus, and Staphylococcus epidermidis Antifungal activity against C. albicans	Soil from Burg-Arab, Alexandria, Egypt	⁶⁷
Treponemycin		Macrolide	Streptomyces sp. MS-6-6	Broad spectrum antibacterial activity, including Mycobacterium tuberculosis Antifungal activity against C. albicans	Soil from the western region of Saudi Arabia	⁶⁸
Bacitracin derivative (N/A)	N/A	Peptide	Bacillus licheniformis BL1 inhabiting the rhizosphere of wheat plants	Broad-spectrum antibacterial activity against MDR UTI pathogens	Rhizospheric soil from Baghdad, Iraq	⁶⁹
Thuricin Bn1 (N/A)	N/A	Peptide	Bacillus thuringiensis subsp. kurstaki Bn1 (Bt-Bn1) isolated from insect Balaninus nucum	Antibacterial activity against B. cereus, Bacillus weinhensteph-enensis, Listeria monocytogenes, Pseudomonas savastanoi, Pseudomonas syringae, Paucimonas lemoignei, and Bacillus thuringiensis	Hazelnut trees, Black Sea Region, Turkey	⁷⁰

Abbreviation: MENA, Middle East and North Africa.

Table 3.

Compounds Derived from Marine bacteria Inhabiting the MENA Region.

Compound	Structure	Class	Producer	Mode of action	Location	Reference
Pyrrole derivative	N/A	Pyrrole	Streptomyces sp. MN41	Antibacterial activity against MRSA	Caspian Sea, Iran	⁷¹
Olivomycin A analog SP 85	N/A	Ketone	Streptomyces sp. strain SP 85 inhabiting the marine sponge Dysidea avara	Antibacterial activity against M. luteus and B. cereus	Persian Gulf, Larak Island, Iran	⁷²
Carotenoid pigment	N/A	Carotenoid	Micrococcus sp. MP76	Antibacterial activity against P. aeruginosa, E. coli, and S. aureus	Persian Gulf, Coast of Bushehr Province, Iran	⁷³
Persiamycin A		Quinone	Streptomonospora sp. PA3 inhabiting the sponge Nipahtes furcata	Antibacterial activity against S. aureus, Klebsiella pneumoniae, and P. aeruginosa	Persian Gulf, Coast of Nayband Gulf, Iran	⁷⁴
(4aR,7R,8R,8aS)-2-heptylhexahydropyrano [3,2-d][1,3]dioxine-67,8-triol	N/A	Polyketide	Streptomyces sp. SCA-7	Antibacterial activity against Enterococcus sp.	Arabian Gulf, Coast of Alkhobar, Saudi Arabia	⁷⁵
Actinomycins D (45), X_0β and X₂		Peptide	Streptomyces heliomycini WH1	Antibacterial activity against B. subtilis, B. cereus, and MRSA	Arabian Gulf, Coast of Jobail, Saudi Arabia	⁷⁶
3-(3,5-Dichloro-4-hydroxyphenyl)propanoic acid (46), 3-(3,5-dichloro-4-hydroxyphenyl) propanoic acid methyl ester (47) and 3-(3-chloro-4-hydroxyphenyl)propanoic acid (48)		Phenylpropanoid	Streptomyces coelicolor LY001 inhabiting the sponge Callyspongia siphonella	Antibacterial activity against S. aureus and E. coli	Red Sea, Coast of Jizan, Saudi Arabia	⁷⁷
cyclo(L-Phe-trans-4-OH-L-Pro) (49) and cyclo(L-Phe-cis-4-OH-D-Pro) (50)		Diketopiperazine		Antifungal activity against C. albicans	Red Sea, Coast of Jizan, Saudi Arabia	⁷⁷
Lyngbic acid		Fatty Acid	Cyanobacterium Moorea producens	Antibacterial activity against Mycobacterium tuberculosis	Red Sea, Coast of Jeddah, Saudi Arabia	⁷⁸
Lyngbyabellin G		Depsipeptide	Cyanobacterium Okeania sp.	Antiparasitic activity against Plasmodium falciparum	Red Sea, Algetah Alkabira reef, Jeddah, Saudi Arabia	⁷⁹
Aqabamycins E (53) and F (54)		Maleimide	Vibrio sp. WMBA-1 isolated from the surface of the soft coral Sinularia polydactyla	Antibacterial activity against B. subtilis, M. luteus, E. coli, and Proteus vulgaris	Red Sea, Coast of Aqaba, Jordan	^{80, 81}
Actinosporin A		Angucycline	Actinokineospora sp. EG49 inhabiting the sponge Spheciospongia vagabunda	Antiparasitic activity against Trypanosoma brucei	Red Sea, Egypt	⁸²
Fridamycin H		Angucycline	Actinokineospora spheciospongiae sp. nov. DSM 45935 T inhabiting the sponge Spheciospongia vagabunda	Antiparasitic activity against Trypanosoma brucei strain TC221	Red Sea, offshore Ras Mohamed, Egypt	⁸³
Dimethyl phenazine-1,6-dicarboxylate and phenomycin	N/A	Phenazine	Micromonospora sp. UR56 inhabiting the sponge Callyspongia sp.	Antibacterial and antibiofilm activities on S. aureus via inhibition of Gyrase B and Pyruvate kinase	Red Sea, Coast of Ras Mohamed, Egypt	⁸⁴
p-Anisamide		Phenazine		Antibacterial and antibiofilm activities on S. aureus and P. aeruginosa	Red Sea, Coast of Ras Mohamed, Egypt	⁸⁴
Saadamycin		Pyranone	Streptomyces sp. Hedaya48 inhabiting the sponge Aplysina fistularis and the derived mutant Ah22	Antifungal activity against clinical dermatophytes isolates	Red Sea, Coast of Sharm El-Sheikh, Egypt	⁸⁵
Undecylprodigiosin		Alkaloid	ESRAA-10 and ESRAA-31, endophytic Streptomyces of the soft coral Dendronephthya hemprichi and their recombinant strain Streptomyces sp. ALAA-R20	Antibacterial activity against MDR Pseudomonas sp. and MDR S. aureus MRSA Antifungal activity against dermatophytes	Red Sea, Coast of Hurghada, Egypt	⁸⁶
Ayamycin		Ketone	Nocardia sp. ALAA 2000 inhabiting the marine red alga Laurenica spectabilis	Broad-spectrum antibacterial and antifungal activity	Red Sea, Coast of Ras-Gharib, Egypt	⁸⁷
Justicidin B		Quinone
Asphodelin (62) and Crysophanol 8-methyl ether		Quinone
Essramycin		Triazolopyrimidine	Streptomyces sp. Merv8102	Broad-spectrum antibacterial activity	Mediterranean Sea, Platinum Coast, Egypt	⁸⁸
Mersaquinone		Tetracene	Streptomyces sp. EG1	Antibacterial activity against MRSA	Mediterranean Sea, Coast of Mersa Matruh, Egypt	⁸⁹
7-Methylcoumarin		Benzopyrone	Streptomyces sp. F2 recombinant of Streptomyces sp. Merv 1996 and 7409 isolated from jellyfish	Antibacterial activity against S. aureus, B. subtilis, M. luteus	Mediterranean Sea, Coast of El-Agami, Egypt	⁹⁰
Quercetin-7,3′-dimethylether				Antifungal activity against Aspergillus niger and Botrytis fabae
Cirsimaritin				Antifungal activity against Rhodotorula minuta, Platythyrea angusta, Cryptococcus neoformans, and C. albicans
[2-Hydroxy-5-((6-hydroxy-4-oxo-4H-pyran-2-yl)methyl)-2- propylchroman-4-one]	N/A	Polyketide	Streptomyces sundarbansensis WR1L1S8 inhabiting the marine brown alga Fucus sp.	Antibacterial activity on MRSA	Mediterranean Sea, Coast of Bejaia, Algeria	^{91, 92}
Arenaric acid, K41 A, and A-32887		Polyether Polyketides	Streptomyces cacaoi 14CM034	Antibacterial Activity on MRSA, E. coli, P. aeruginosa, and Enterococcus faecium Antifungal activity on C. albicans	Mediterranean Sea, Coast of Mersin, Turkey	⁹³
1,6-Dihydroxyphenazine		Phenazine	Nocardiopsis sp. RV163 inhabiting the sponge Dysidea avara when co-cultivated with Actinokineospora sp. EG49	Antibacterial activity against Bacillus sp. Antiparasitic activity against Trypanosoma brucei	Mediterranean Sea	⁹⁴

Abbreviations: MRSA, Methicillin-resistant S. aureus; MENA, Middle East and North Africa.

Terrestrial Bacteria

When it comes to soil prokaryotes, Tunisia has shown its potency as an invaluable source of antimicrobial SMs. A first example is Streptomyces sp. TN82, isolated from the Tunisian Sahara, which synthesizes a variety of NPs. Two were of interest: 3-Phenylpyrazin-2(1H)-one, a pyrazine which has never before been reported to occur naturally, and 3-O-methylviridicatin, a quinolin-2-one with a phenyl at position 4 and a methoxy group at position 3, previously isolated from a Penicillium sp.⁹⁵ 3-Phenylpyrazin-2(1H)-one (Structure 28) and 3-O-methylviridicatin (Structure 29) both exhibited antibacterial activity against S. aureus ATCC 6538 (MIC of 4 and 4.5 μg/mL), Listeria monocytogenes ATCC 19117 (MIC of 1 and 9 μg/mL), and Salmonella typhimurium ATCC 14028 (MIC of 2 and 4.5 μg/mL). 3-Phenylpyrazin-2(1H)-one was more efficient than ampicillin against L. monocytogenes and S. typhimurium, but not against S. aureus while 3-O-methylviridicatin was less potent than the reference drug against all 3 pathogens.⁶¹

A second instance is that of Streptomyces sp. TN256, another inhabitant of the Tunisian Sahara that secretes an assortment of antimicrobial NPs. This collection of metabolites has all been previously described and comprises: the alkene 1-nonadecene (Structure 32),⁹⁶ previously isolated from the plant Rosa damascena, the alkaloid derivative N-[2-(1H-indol-3-yl)-2 oxo-ethyl] acetamide (Structure 30), purified from cultures of Streptomyces anulatus,⁹⁷ the phthalate derivative di-(2-ethylhexyl) phthalate (Structure 31) obtained formerly from the plant Aloe vera Linne,⁹⁸ and the diketopiperazine Cyclo (L-Pro-L-Tyr) (Structure 33), a hexahydropyrrolo[1,2-a] pyrazine-1,4-dione with a hydroxylated benzyl, which was shown to be produced earlier by the actinomycete strain A8.⁹⁹ All of these four compounds inhibited the growth of Gram-positive (Micrococcus luteus LB 14110 and S. aureus ATCC 6538) and Gram-negative (E. coli ATCC 8739 and Salmonella enterica ATCC 43972) bacteria, as well as the fungus Fusarium sp., with zones of inhibition ranging between 10 and 21 mm in diameter.⁶² Another Streptomyces found in the Tunisian Sahara at an oasis is Streptomyces misionensis V16R3Y1. This microorganism produced the diketopiperazine cyclo (L-Leu-L-Pro) (Structure 34), a hexahydropyrrolo[1,2-a]pyrazine-1,4-dione with 2-methyl propyl at position 3, which has been previously isolated from a Bacillus strain.¹⁰⁰ This compound demonstrated broad-spectrum yet moderate antibacterial and antifungal activity.⁶³ Another bacterial strain was isolated from a soil sample in south Tunisia and was deciphered to be Streptomyces sp. TN262. This strain generated two known macrolides, Cineromycin B (Structure 35) and its derivative 2,3-Dihydrocineromycin B (Structure 36), previously isolated from a Streptomyces species,¹⁰¹ which are branded with a tetramethyl-1-oxacyclotetradeca-36,9-trien-2-one with two hydroxy groups at positions 5 and 8. They both inhibited the growth of M. luteus LB 14110 and S. aureus ATCC 6538 with 12 to 13 mm inhibition zones. Additionally, Streptomyces sp. TN262 produced Tryptophol (Structure 37), a known aromatic alcohol,¹⁰² that showed antibacterial activity against S. enterica ATCC 43972 with a 12-mm zone. Moreover, it inhibited the previously mentioned Gram-positive pathogens, but with more potency than Cineromycins. Besides, Tryptophol inhibited the growth of Fusarium sp. with a 12-mm zone.⁶⁴

Another country in the Maghreb region where soil bacteria have provided a promising source of antimicrobial NPs is Algeria. One example is Streptomyces sp. HG29, which was isolated from Algerian Saharan soil. This strain synthesized two known macrolides Oligomycins A (Structure 38),¹⁰³ and E (Structure 39),¹⁰⁴ which are typically produced by other Streptomyces species. These compounds inhibited the growth of several species of Aspergillus, Fusarium, and Penicillium with MICs below 30 mg/mL and were comparable in potency to the utilized control drugs Amphotericin B and Itraconazole.⁶⁵ Another case is the bacterium Nocardiopsis sp. HR-4 isolated from salt-lake soil in the Algerian desert. This strain secreted two angucyclinones: the known ( − )-8-O-methyltetrangomycin (Structure 40)¹⁰⁵ and the novel ( − )-7-deoxy-8-O-methyltetrangomycin (Structure 41), which are characterized by a 2,4-dihydrobenzo[a]anthracene-1,7,12-trione core structure. Both of these compounds showed antibacterial activity against Gram-positive bacteria S. aureus ATCC 25923 and 43300, Enterococcus faecalis ATCC 29212, and M. luteus ATCC 4698, with zones of inhibition having diameters between 23 and 41 mm.⁶⁶

Moving east in the African continent, specifically to Egypt, a Streptomyces species labeled MAR01 was isolated from a soil sample from Burg-Arab, Alexandria. This strain produced a novel antibiotic named Meroparamycin (Structure 42), comprising a benzene ring connected to an amido group at C1 and a branched aliphatic ketone at C4. This compound showed antibacterial activity against B. subtilis ATCC 6633, S. aureus ATCC 29737, Staphylococcus epidermidis ATCC 12228, and M. luteus ATCC 9341 with MICs ranging from 3.13 to 12.5 mg/mL. It also inhibited the growth of the Gram-negative bacterium E. coli ATCC 10536 and the fungus C. albicans ATCC 10231 with MICs of 50 and 25 mg/mL, respectively.⁶⁷ In Saudi Arabia, a different Streptomyces sp., called MS-6–6, was found in a soil sample originating from the western region of the country. This strain was capable of producing a known macrolide antibiotic treponemycin, characterized by a macrocyclic lactone ring with a nitrile group and a diene function, previously isolated from Daldinia cf concentrica.¹⁰⁶ Treponemcyin (Structure 43) proved to be a broad-spectrum antibiotic inhibiting various bacteria with relatively low MIC values: less than 2.9 μg/mL for Gram-positive pathogens and less than 26.7 μg/mL for Gram-negative bacteria. However, this antibacterial agent attracted research for its anti-tuberculous activity as it inhibited the growth of Mycobacterium tuberculosis ATCC 25177, with a MIC of 4.17 μg/mL. Additionally, this molecule demonstrated antifungal capacity against C. albicans with a MIC of 13.3 μg/mL, and, although the cytotoxicity of the pure compound was not assessed, the crude extract of strain MS-6-6 was found to be non-toxic toward the normal human fetal lung fibroblast cell line (MRC-5), thus projecting the low toxicity of Treponemcyin.⁶⁸

Heading north of the Arabian Peninsula, to Iraq, the microbial population of rhizospheric soil of wheat plants from the capital city of Baghdad was studied. One of the isolated strains, Bacillus licheniformis BL1, synthesized a novel bacitracin derivative peptide antibiotic. This compound showed broad-spectrum antibacterial activity against MDR-UTI (urinary tract infection) causing clinical isolates including Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and E. coli.⁶⁹ On the other hand, another terrestrial bacterium that led to the discovery of a pure novel antibacterial agent is Bacillus thuringiensis subsp. kurstaki Bn1 (Bt-Bn1) isolated from the insect Balaninus nucum, a common pest of the hazelnut tree in the Black Sea region of Turkey. The new compound was named Thuricin Bn1 and was characterized as being a Bacteriocin that inhibited the development of various plant phytopathogenic bacteria and spoilage microorganisms.⁷⁰

Marine Bacteria

The bacteria inhabiting the seas of the MENA region have shown a noteworthy capacity to produce functionally varied NPs. On the northern coast of Iran, from the Caspian Sea, the strain Streptomyces sp. MN41 was isolated. This bacterium synthesizes a previously uncharacterized pyrrole derivative, which exhibits bactericidal effects against Methicillin-resistant S. aureus (MRSA) ATCC 33591 with a MIC of 2.8 μg/mL and an MBC (minimal bactericidal concentration) of 5.62 μg/mL.⁷¹ However, it is Iran's southern coast outlining the Persian Gulf that is the source of marine bacteria with powerful antimicrobial SMs. From Larak island, a Streptomyces sp. strain SP 85, inhabiting the marine sponge Dysidea avara, was found to secrete a novel olivomycin A derivative known as SP 85. This antibacterial molecule possesses a tricyclic chromophore/aglycon connected to a disaccharide at C6 and a trisaccharide at C2. It demonstrated inhibition against M. luteus and B. cereus, while showing low levels of cytotoxicity against the normal cell human umbilical vein endothelial cell line HUVECs.⁷² From the shore of Bushehr Province, Micrococcus sp. MP76 was found. This strain produced a carotenoid pigment that inhibited the growth of S. aureus ATCC 25923, E. coli ATCC 25922, and P. aeruginosa ATCC 27853 with IC50 values of 3.4, 4.8, and 4.8 mg/mL, respectively.⁷³ Streptomonospora sp. PA3 inhabited a sponge that was recovered from the coast of Nayband. A novel aromatic polyketide was isolated from this bacterium and denoted as Persiamycin A (Structure 44). It is a tetracyclic anthraquinone with hydroxyl groups at C1, C3, C8, and C11, which inhibits the growth of S. aureus ATCC1337, K. pneumoniae ATCC1290, and P. aeruginosa ATCC1310, with inhibition zones of around 9 mm.⁷⁴

It has been shown progressively that the Saudi Arabian coast of the Arabian Gulf (Persian Gulf) shelters bacteria with antimicrobial metabolites. One example is that of Streptomyces sp. SCA-7 from the coast of the city of Alkhobar. This strain synthesized the novel polyketide (4aR,7R,8R,8aS)-2-heptylhexahydropyrano[3,2-d][1,3]dioxine-67,8-triol, which showed antibacterial activity against Enterococcus sp. comparable to that of streptomycin.⁷⁵ Another case is that of Streptomyces heliomycini WH1 from the coast of the city of Jobail, which produces multiple well-known actinomycins, namely D (Structure 45), X0β, and X2.^107‐109 These compounds possess bicyclic chromopeptide lactones sharing the chromophoric phenoxazinone dicarboxylic acid to which are attached two pentapeptide lactones of nonribosomal origin and are known to be synthesized by soil-inhabiting microorganisms. Actinomycin X2 was the most potent among the three isolated compounds with MICs lower than 0.15 μM against Gram-positive pathogens B. subtilis ATCC 6051, B. cereus ATCC 14579, and S. aureus ATCC 6538 and ATCC 43300 (MRSA), even surpassing the antimicrobial efficacy of Ciprofloxacin. All of these compounds isolated from WH1 also demonstrated low levels of cytotoxicity on normal human embryo liver cells L02.⁷⁶

Nevertheless, the highest number of pure compounds have originated from bacteria that live in the Red Sea. A first instance is Streptomyces coelicolor LY001 inhabiting the sponge Callyspongia siphonella collected off the coast of Jizan, Saudi Arabia. This strain was able to synthesize three new natural 3-phenylpropanoic acid derivatives: 3-(3,5-dichloro-4-hydroxyphenyl) propanoic acid (Structure 46), 3-(3,5-dichloro-4-hydroxyphenyl) propanoic acid methyl ester (Structure 47), and 3-(3-chloro-4-hydroxyphenyl) propanoic acid (Structure 48). These phenylpropanoids all demonstrated antibacterial activity against S. aureus ATCC 25923 (MICs between 32 and 64 μg/mL) and E. coli ATCC 25922 (MICs between 16 and 32 μg/mL), yet they were all less potent than Ciprofloxacin. Additionally, S. coelicolor LY001synthesizes the known cyclo(L-Phe-trans-4-OH-L-Pro) (Structure 49),¹¹⁰ and cyclo(L-Phe-cis-4-OH-D-Pro) (Structure 50),¹¹¹ which were previously isolated from bacterial endophytes of spider mites and sponges, respectively. These compounds possess a hexahydropyrrolo[1,2-a]pyrazine-1,4-dione with a benzyl at position 3 and a hydroxy group at position 7. These diketopiperazines inhibited the growth of C. albicans ATCC 14053 with MICs of 32 μg/mL, thus less efficiently than Ketoconazole.⁷⁷ The Saudi Red Sea also houses cyanobacteria with antimicrobial metabolites such as Moorea producens isolated from the coast of Jeddah which secretes lyngbic acid (Structure 51). This compound is also known as (S)-7-methoxytetradec-4(E)-enoic acid and was previously isolated from the same bacterial species.¹¹² It showed antibacterial activity against M. tuberculosis H37Rv ATCC 27294 inhibiting 65% of bacterial cells at a concentration of 12.5 μg/mL.⁷⁸ Additionally, an Okeania species isolated from the coast of the same city at the level of Algetah Alkabira reef produced Lyngbyabellin G (Structure 52). This depsipeptide was isolated from the same species in the past¹¹³ and was characterized by having an esterized cycle containing 2 thiazole groups with a 4,4-dichloropentyl attached at position 12. Besides, it effectively inhibited the growth of the parasite Plasmodium falciparum strain FCR-3 with an IC50 of 1.1 μM.⁷⁹

From the Red Sea in south Jordan near Aqaba, the Vibrio sp. WMBA-1 was isolated from the surface of the soft coral Sinularia polydactyla. Although this strain synthesized seven novel nitro maleimides, 2 were of main interest as anti-infective agents: Aqabamycins E (Structure 53) and F (Structure 54). The latter has a hydroxylated nitro maleimide connected to two identical nitro-hydroxy-phenyl groups, one at C3 and the other at C4. The former has a similar structure except that the group at C4 is a non-substituted phenyl.⁸⁰ Both these compounds present antibacterial activity against B. subtilis, M. luteus, E. coli, and Proteus vulgaris with MICs below 12.5 μg/mL for Aqabamycin E and below 25 μg/mL for Aqabamycin F.⁸¹

Nonetheless, the discovery of bioactive material from the Red Sea has been predominantly led by Egyptian researchers. Numerous pure antimicrobial NPs have been found from the Egyptian coast of the Red Sea. Actinosporin A (Structure 55), a novel O-glycosylated angucycline was isolated from Actinokineospora sp. EG49 inhabiting the sponge Spheciospongia vagabunda. This compound is a tetrahydroxylated tetracyclic anthraquinone to which is attached a trihydroxy-methyl-oxanyl at C4 through an O bond.⁸² The same sponge species was recovered offshore Ras Mohamed, Egypt, and was found to contain Actinokineospora spheciospongiae sp. nov. DSM 45935 T. This bacterium was shown to produce the novel angucycline Fridamycin H (Structure 56), a similar compound to Actinosporin A with a monohydroxylated anthraquinone with a trihydroxy-methyl-oxanyl attached at C4 through an O bond and a hydroxy-methyl-butyric acid attached at C8.⁸³ Both Actinosporin A and Fridaymycin H exhibited antiparasitic activity against Trypanosoma brucei strain TC221 after 48 h with IC50 values of 15.47 and 7.18 µΜ, respectively. Neither compound showed cytotoxicity when tested against J774.1 macrophages.^82,83 From the coast of Ras Mohamed, Micromonospora sp. UR56 inhabiting a sponge of the Callyspongia genus was isolated. This strain secretes multiple compounds with three phenazines proving their importance as antimicrobial agents. First, there are dimethyl phenazine-1,6-dicarboxylate and phenazine-1,6-dicarboxylic acid monomethyl ester (phenomycin), which were previously isolated from Streptomyces fervens var. phenomyceticus and Pseudomonas phenazinium, respectively.^114,115 Both of these compounds demonstrated an ability to inhibit the growth and biofilm formation of S. aureus ATCC 9144.⁸⁴ Second, there is the known p-anisamide (Structure 57), also known as 4-methoxybenzamide.¹¹⁶ This molecule proved to be efficient in inhibiting the growth and biofilm formation not only of S. aureus ATCC 9144, but also of P. aeruginosa ATCC27853. However, as antibacterials, these molecules were less efficient in inhibiting the growth of bacterial pathogens when compared to Gentamicin.⁸⁴

Other bacteria have also emerged from the Egyptian coast of the Red Sea. The coast of Sharm El-Sheikh is the place of origin of Streptomyces sp. Hedaya 48 inhabiting the sponge Aplysina fistularis. This strain produced the novel antimycotic agent Saadamycin {4-(hydroxymethyl)-5-hydroxy-2H-pyran-2-one} (Structure 58). This compound inhibited the growth of clinical dermatophyte isolates including isolates from the genera Aspergillus and Candida with MIC values below 5 μg/mL and MFC values below 10 μg/mL. This compound was proven to be more effective than the clinically utilized antifungal. Myconazole, whose MIC and MFC (minimal Fungicidal Concentration) values were in the mg/mL range.⁸⁵ Other Red Sea Streptomyces strains were isolated from their host, the soft coral Dendronephthya hemprichi, at the coast of Hurghada, Egypt, and were called ESRAA-10 and ESRAA-31. These bacteria synthesized Undecylprodigiosin (Structure 59), whose production was amplified in recombinant strain ALAA-R20 after successful gene transfer was performed on it. Undecylprodigiosin is a known alkaloid previously isolated from Streptomyces lividans,¹¹⁷ characterized by 3 pyrrole rings connected to an undecane saturated chain. It demonstrated antibacterial activity against MDR S. aureus and Pseudomonas sp., as well as MDR dermatophytes with MICs ranging between 0.5 and 4.0 μg/mL. Moreover, Undecylprodigiosin showcased relatively low MBC and MFC values against these MDR pathogens (< 8 μg/mL), revealing its potential cidal action against the said microbes.⁸⁶ However, Red Sea bacteria do not only inhabit corals and sponges, but they also live as endophytes/epiphytes of algae such as in the case of Nocardia sp. ALAA 2000 inhabiting the marine red alga Laurenica spectabilis, which was collected off the coast of Ras-Gharib, Egypt. This strain can be considered as a factory for antimicrobial NPs synthesizing several powerful SMs. For example, this bacterium produced two peri-hydroxy-anthraquinones, Asphodelin (4,7’-bichrysophanol, Structure 62),¹¹⁸ and Crysophanol 8-methyl ether,¹¹⁹ which were previously isolated from the plants Asphodelus microcarpus and Eremurus chinensis, respectively. Also, it produced the arylnaphthalene lignanolide justicidin B (Structure 61), which was previously isolated from a Hoplophyllum (Rutaceae) species.¹²⁰ Besides, it gave birth to the novel compound 1,1-Dichloro-4-ethyl-5-(4-nitro-phenyl)-hexan-2-one, which was called Ayamycin by the authors. All four of these NPs demonstrated potent antimicrobial capacities on multiple representatives of Gram-positive and Gram-negative bacteria, as well as a wide range of fungi. Ayamycin (Structure 60) proved to be the most significant inhibitor of microbial growth, with MIC values below 0.5 μg/mL against all of the tested pathogens.⁸⁷

Egypt has another coastal line on its northern border. This Mediterranean Egyptian coast is the homeland of multiple bacteria with antimicrobial potential. Streptomyces sp. Merv8102 isolated off the Platinum coast in Egypt is a good example. It synthesized the first triazolopyrimidine antibiotic isolated from nature, named Essramycin (Structure 63). This compound inhibited the growth of Gram-positive bacteria with MIC values around 1 μg/mL, while it inhibited that of E. coli ATCC 10536 and P. aeruginosa ATCC 10145 with MIC values of 8 and 3.5 μg/mL, respectively,⁸⁸ although another research team debunked these results.¹²¹ Another sample of putative microbes from the Egyptian Mediterranean coast is Streptomyces sp. EG1, isolated from the port city of Mersa Matruh. This strain is the producer of a novel tetracene derivative Mersaquinone (Structure 64), a tetracyclic anthraquinone with hydroxyl groups at C3, C8, C10, and C11, as well as a methyl group at C13. Mersaquinone meaningfully inhibited the growth of the MRSA strain TCH1516 with a MIC value of 3.36 μg/mL; nonetheless, this compound was less efficient than the reference drug Ciprofloxacin, whose MIC against MRSA was 0.93 µM.⁸⁹ Another impressive microbial factory whose origin is from the Egyptian Mediterranean coast was Streptomyces sp. F2. Although this recombinant strain was created in the laboratory, its parent strains, Streptomyces sp. Merv 1996 and 7409, were isolated from a jellyfish off the coast of El-Agami. Streptomyces sp. F2 generated 3 benzopyrone derivatives, which are known to be plant metabolites, and whose antimicrobial activities were investigated. The first was the heterocyclic compound 7-methylcouramin (Structure 65), which inhibited the growth of Gram-positive bacteria S. aureus ATCC 6538, B. subtilis ATCC 6051, and M. luteus ATCC 9341, with MIC values of 0.8, 3.6, and 2 μg/mL, respectively. The second was Quercetin-7,3′-dimethyl ether (Structure 66), also known as 2-(3,4-dihydroxyphenyl)-5-hydroxy-3,7-dimethoxychromen-4-one, which inhibited the growth of filamentous fungi A. niger and Botrytis fabae with MICs of 1 and 2.5 μg/mL, respectively. The third was Cirsimaritin (Structure 67) {5-hydroxy-2-(4-hydroxyphenyl)-6,7-dimethoxychromen-4-one}, which suppressed the growth of Rhodotorula minuta, Platythyrea angusta, Cryptococcus neoformans, and C. albicans with a MIC value of 1 μg/mL.⁹⁰

However, it is not only the Egyptian coast of the Mediterranean that offers bacteria with an extensive arsenal of antimicrobial NPs. Other countries’ coasts on the Mediterranean Sea basin also house such organisms. Algeria is a prime illustration where the strain Streptomyces sundarbansensis WR1L1S8, an endophyte of a marine brown alga of the Fucus genus was isolated off the coast of Bejaia. Although this strain made a plethora of antimicrobial agents, one particularly stood out as a novel anti-MRSA polyketide compound [2-hydroxy-5-((6-hydroxy-4-oxo-4H-pyran-2-yl)methyl)-2-propylchroman-4-one].^91,92 This molecule interestingly inhibited the growth of MRSA ATCC 43300 without affecting that of the Methicillin-sensitive S. aureus (MSSA) ATCC 25923. Regardless, this molecule was less effective against MRSA than both Vancomycin and Gentamicin.⁹¹ Another case is seen in Turkey where Streptomyces cacaoi 14CM034 was isolated off the coast of Mersin. This bacterium engendered 3 polyether compounds: two previously isolated from bacteria named Arenaric acid (Structure 68),¹²² and K41 A,¹²³ while the third A-32887, although known synthetically, was never before discovered from a natural source. All of these polyketides exhibited antimicrobial activities against the Vancomycin-Resistant Enterococcus faecium DSM13590 (VRE), E. coli O157:H7, MRSA S. aureus DSM11729, P. aeruginosa ATCC27853, and C. albicans DSM5817. K41 A was the most effective against the Gram-positive pathogens (MICs range between 0.11 and 1.79 μg/mL), while A-32887 was the best anti-yeast compound.⁹³ Moreover, a Mediterranean Nocardiopsis sp. RV163, a symbiote of the sponge Dysidea avara, was able to produce 1,6-dihydroxyphenazine (Structure 69), when co-cultivated with the Red Sea inhabiting Actinokineospora sp. EG49. This molecule showcased an antibacterial activity against Bacillus sp. P25 (11 mm inhibition zone) and an antiparasitic activity against T. brucei (IC50 value of 19 μM).⁹⁴

Geological Distribution of Antimicrobial NPs in the MENA Region

In a first effort to improve the chances of discovering new antimicrobial SMs, we thought that excavating for environmental microbes in previously unexploited locations was necessary. Therefore, the research output of various groups across the MENA region, whether they resulted in obtaining pure compounds or not, were visualized on a map, as seen in Figure 1. It was then evident that the Red Sea represented an abundantly active zone when it comes to NP discovery, especially at the level of its west (Egyptian) coast, as seen in Figure 2. However, the rest of the region was sparsely examined, with entire countries left untouched. Nonetheless, these countries represent incomparable opportunities for NP discovery due to their elevated levels of biodiversity and their unique variability of niches. Examples include Mauritania, a desert-filled African country with a coast on the Atlantic. Another instance encompasses the heart of the Levant, specifically Lebanon and Syria, which possess coasts on the Mediterranean while being rich in mountain ranges as well as green forests. Hence, these countries, among other understudied areas, should be considered for the mining of new microbial genera, species, or strains to harvest novel classes of antimicrobial metabolites.

Figure 1.

A map of the distribution of extracts, fractions, and compounds derived from environmental microbes inhabiting the MENA region. Abbreviation: MENA, Middle East and North Africa.

Figure 2.

A map of the distribution of extracts, fractions, and compounds derived from environmental microbes inhabiting the MENA region with a focus on those living at the level of the red sea basin and coasts. Abbreviation: MENA, Middle East and North Africa.

Methods to Improve the Discovery of Antimicrobial NPs in the MENA Region

In a further effort to enhance the discovery of antimicrobial NPs from microorganisms inhabiting the MENA region, several modern approaches could be utilized. The three main methodologies are described below, highlighting for each the benefits as well as the disadvantages.

Metagenomics

Metagenomics is a culture-independent genomic analysis of microbial communities, which relies on the direct extraction of DNA from environmental samples. This environmental DNA (eDNA) can be subsequently sequenced and analyzed, enabling researchers to understand the microbial composition of the studied sample. Additionally, this metagenome reflects the genomically encoded capacities of the present microbes. Moreover, metagenomic libraries could be created by shotgun cloning of random parts of the eDNA into sufficient vectors, which can then be inserted into a suitable bacterial host. The metabolites of the generated clones are consequently screened for their antimicrobial biological activities.¹²⁴ Direct genomic cloning offers an opportunity to capture operons or genes that encode pathways that may lead to the synthesis of complex molecules, such as antibiotics.¹²⁵ The biosynthetic pathways of these novel bioactive metabolites can then be further dissected by interpreting metagenomic sequencing data.¹²⁴

The usage of such metagenomic procedures has revolutionized the drug discovery procedure in biological sciences. They significantly enhanced the development of numerous antimicrobial NPs originating from various environmental niches.¹²⁶ This improvement in discovery is the result not only of the functional screening of clones but also through information generated on microbial metabolism, which inspires new antimicrobials synthesis via heterologous expression.¹²⁷

Both novel and previously isolated antibiotics have been detected by functional screens from metagenomic libraries.^128‐131 Among the previously unexploited compounds, turbomycin was one of the first antibiotics discovered by metagenomics. It was identified by accident in a clone that had hemolytic activity as part of a basic study directed toward rationalizing the prevalence of hemolysins among cultured soil bacteria.¹²⁸ Another example is that of violacein, a broad-spectrum antibiotic initially identified in a metagenomic clone of Chromobacterium violaceum. This antibacterial agent showed activity against S. aureus, Bacillus sp., and Streptococcus sp.¹³⁰

This bioinformatics tool offers an upper edge by saving time and reducing reliance on microbial culture in laboratories, making it possible to explore bioactive compounds from organisms that are resistant to cultivation.¹³² Although the benefits of metagenomics research are evident, this approach also has notable limitations. It includes low resolution, bias classification of short target segments, and false functional confirmation.¹²⁴ Besides, metagenomics is expensive, labor-intensive, and requires sterling skills for wet-lab.¹³³

High-Throughput Screening

High-Throughput Screening (HTS) is a drug discovery technique that has gained widespread popularity over the past two decades, becoming a standard tool in the pharmaceutical industry. It is a method of screening and assaying a large number of biological modulators and effectors against selected and specific targets.¹³⁴ Due to the need to process thousands of assays per day, HTS has revolved around the combined field of multiple-well microplates and robotic processing.¹³⁵ HTS utilizes a variety of biological assays to find lead compounds. These include microbiological techniques like broth microdilution or biofilm formation assay which facilitate the discovery of new antibacterial, antifungal and antibiofilm agents.¹³⁶

Itoh et al developed a high-throughput strategy which led to the discovery of potent analogs of the antibiotic lysocin E. These compounds were demonstrated to be superior agents for the treatment of infectious diseases caused by Gram-positive bacteria, including MRSA.¹³⁷ On the other hand, Maraviroc was identified as the most promising hit against the Human Immunodeficiency Virus (HIV-1) after HTS of the Pfizer file collection.¹³⁸

The acts of miniaturization and automation of HTS help to reduce the use of reagents, minimize or remove labor-intensive steps, and greatly reduce the cost of research.¹³⁹ Nevertheless, the primary advantage of the HTS method remains in the speeding up of the discovery process.¹⁴⁰ Furthermore, this method plays an important role in the early stages of drug development, providing a qualitative and quantitative characterization of compound libraries and analytical support for preclinical and clinical absorption, distribution, metabolism, excretion (ADME) studies. HTS, therefore, facilitates the early elimination of unsuitable compounds. Yet, as HTS can simultaneously administrate multiple drugs together, a false apparent activity of a certain compound could be observed during screening, might it be an enhanced or a discouraged one.¹⁴¹

Molecular Modeling

Drug discovery has developed from the classical screening of NPs to more sophisticated modern approaches, namely molecular modeling.¹⁴² This method is a useful tool in many research applications, such as structure elucidation. It relies on theoretical and analytical approaches used to model the structure, properties, and dynamic behavior of molecules at the atomic level.¹⁴³ This branch of science applies the basic laws of physics and chemistry to the study of molecules. The ultimate goal is to create models and simulations that can assist in the various stages of a pipeline of discovery by predicting, rationalizing, and estimating the properties and interactions of molecules, thus enabling a more rational approach to the production of drugs.¹⁴⁴

How is molecular modeling relevant for NP research? Well, although several NPs currently in use have been discovered, the characterization of various drug targets has only been achieved recently. This flow of information contributed immensely to understanding the structure–activity relationships of NPs, as well as their relations to their targets.¹⁴²

Wang et al discovered compound ZINC05683641 as a newly available inhibitor against the New Delhi metallo-beta-lactamase 1 (NDM-1), an enzyme allowing bacteria to resist beta-lactam antibiotics, through molecular modeling. The binding mode and interaction mechanism of ZINC05683641 against NDM-1 were explored at atomic level.¹⁴⁵ Another study used molecular modeling with HIV-1 as a target molecule. Structures similar to known integrase inhibitors were identified which were capable of preventing viral replication.¹⁴⁶

Molecular modeling methods give significant advantages of saving time and expense by enabling thorough characterization and analysis of the expected drug-binding modes and the strength of protein-ligand interactions without the biological risks involved.¹⁴³ Molecular modeling is intended to play an ever more central role in the integration of information on the genetic, structural, biological, or chemical origin, increasing the responsibility for delivering effective medicines and making possible the eagerly awaited increase in the productivity of the pharmaceutical industry.¹⁴⁷ However, regardless that these methods are well established, the accuracy of the force fields used, simulation times, and scoring functions remain a limitation.¹⁴³

Conclusion

Taken together, these data showcase the presence of previously uncultured soil and marine dwelling microorganisms of the MENA region capable of synthesizing a plethora of SMs with antimicrobial activities. However, these microbes only represent a small fraction of the vast pool of novel potential NP manufacturers that inhabit untapped locations within MENA. Therefore, further research that explores unexploited niches and their microbial residents for the discovery of novel antimicrobials is needed and can be improved through the utilization of advanced molecular approaches.

Footnotes

Acknowledgements

The authors thank the graphic designer Asmaa Nabil Al-Ghrawi for her assistance with the figures.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The authors would like to acknowledge the National Council for Scientific Research of Lebanon (CNRS-L) for granting a doctoral fellowship to Bassel Awada and Dany Abi Chahine. The fellowships were offered in collaboration with the American University of Beirut (AUB) and Université Saint-Joseph de Beyrouth (USJ) for Bassel Awada and Dani Aby Chahine, respectively.

ORCID iD

Antoine Abou Fayad

References

Centers for Disease Control and Prevention. About antibiotic resistance. Published 2019. Accessed November 10, 2020. https://www.cdc.gov/drugresistance/about.html

World Health Organization. Antimicrobial resistance. Fact sheets. Published 2020. Accessed November 10, 2020. https://www.who.int/news-room/fact-sheets/detail/antimicrobial-resistance

Hay

Rao

Dolecek

, et al. Measuring and mapping the global burden of antimicrobial resistance. BMC Med. 2018;16(1):78. doi:10.1186/s12916-018-1073-z

Centers for Disease Control and Prevention (U.S.); National Center for Emerging Zoonotic and Infectious Diseases (U.S.); Antibiotic Resistance Coordination and Strategy Unit within the Division of Healthcare Quality Promotion. Antibiotic Resistance Threats in the United States. 2019.

Ricotta

Kwan

. Artemisinin-resistant malaria as a global catastrophic biological threat. In: Inglesby

Adalja

, eds. Global Catastrophic Biological Risks. Current Topics in Microbiology and Immunology, Vol 424. Springer; 2019:33‐57.

World Health Organization. Malaria. Malaria fact sheets. Published 2020. Accessed November 10, 2020. https://www.who.int/news-room/fact-sheets/detail/malaria

Lubell

Dondorp

Guerin

, et al. Artemisinin resistance-modelling the potential human and economic costs. Malar J. 2014;13(1):452. doi:10.1186/1475-2875-13-452

Schnall

Rajkhowa

Ikuta

Rao

Moore

. Surveillance and monitoring of antimicrobial resistance: limitations and lessons from the GRAM project. BMC Med. 2019;17(1):176. doi:10.1186/s12916-019-1412-8

Bassetti

Poulakou

Ruppe

Bouza

van Hal

Brink

. Antimicrobial resistance in the next 30 years, humankind, bugs and drugs: a visionary approach. Intensive Care Med. 2017;43(10):1464–1475. doi:10.1007/s00134-017-4878-x

10.

Dadgostar

. Antimicrobial resistance: implications and costs. Infect Drug Resist. 2019;12:3903–3910. doi:10.2147/IDR.S234610

11.

Nikaido

. Multidrug resistance in bacteria. Annu Rev Biochem. 2009;78:119–146. doi:10.1146/annurev.biochem.78.082907.145923

12.

Magiorakos

Srinivasan

Carey

, et al. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect. 2012;18(3):268–281. doi:10.1111/j.1469-0691.2011.03570.x

13.

Falagas

Bliziotis

Kasiakou

Samonis

Athanassopoulou

Michalopoulos

. Outcome of infections due to pandrug-resistant (PDR) gram-negative bacteria. BMC Infect Dis. 2005;5(1):24. doi:10.1186/1471-2334-5-24

14.

Zhi-Wen

Yan-Li

Man

Wei-Jun

. Clinical treatment of pandrug-resistant bacterial infection consulted by clinical pharmacist. Saudi Pharm J. 2015;23(4):377–380. doi:10.1016/j.jsps.2015.01.001

15.

Shamsuzzaman

. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria and antimicrobial therapy in combination. Bangladesh J Med Microbiol. 2017;9(2):1–2. doi:10.3329/bjmm.v9i2.31348

16.

Schmid

Wolfensberger

Nemeth

Schreiber

Sax

Kuster

. Monotherapy versus combination therapy for multidrug-resistant gram-negative infections: systematic review and meta-analysis. Sci Rep. 2019;9(1):15290. doi:10.1038/s41598-019-51711-x

17.

Karaiskos

Antoniadou

Giamarellou

. Combination therapy for extensively-drug resistant gram-negative bacteria. Expert Rev Anti Infect Ther. 2017;15(12):1123–1140. doi:10.1080/14787210.2017.1410434

18.

Hong

. Experimental induction of bacterial resistance to the antimicrobial peptide tachyplesin I and investigation of the resistance mechanisms. Antimicrob Agents Chemother. 2016;60(10):6067–6075. doi:10.1128/AAC.00640-16

19.

Bliss

Alter

. Bacterial resistance to antibiotics in vivo. I. Incidence of resistance. J Bacteriol. 1959;78(5):671–674. doi:10.1128/jb.78.5.671-674.1959

20.

Bliss

Alter

. Bacterial resistance to antibiotics in vivo. II. Population patterns among Staphylococci. J Bacteriol. 1962;84(1):125–129. doi:10.1128/jb.84.1.125-129.1962

21.

Yan

Chen

Huang

. Preliminary study on in-vitro induction of antibiotic resistance in Helicobacter pylori strains isolated from children. Zhonghua Er Ke Za Zhi. 2007;45(9):708–711.

22.

Gould

MacKenzie

. Antibiotic exposure as a risk factor for emergence of resistance: the influence of concentration. J Appl Microbiol. 2002;92(1):78S–84S. doi:10.1046/j.1365-2672.92.5s1.10.x

23.

Lopez

Leroy

Etievant

Ausseil

Gagnon

Arimondo

. Drug discovery methods. In: Egger

Arimondo

, eds. Drug Discovery in Cancer Epigenetics. Academic Press; 2016:63–95.

24.

Newman

Cragg

. Natural products as sources of new drugs over the nearly four decades from 01/1981 to 09/2019. J Nat Prod. 2020;83(3):770–803. doi:10.1021/acs.jnatprod.9b01285

25.

Davies

. Origins and evolution of antibiotic resistance. Microbiol Mol Biol Rev. 2010;74(3):1092–2172. doi:10.1128/MMBR.00016-10

26.

Chin

Balunas

Chai

Kinghorn

. Drug discovery from natural sources. AAPS J. 2006;8(2):E239–E253. doi:10.1007/BF02854894

27.

Pink

Hudson

Mouriès

Bendig

. Opportunities and challenges in antiparasitic drug discovery. Nat Rev Drug Discov. 2005;4(9):727–740. doi:10.1038/nrd1824

28.

Calderone

Sun

Gay-Andrieu

, et al. Antifungal drug discovery: the process and outcomes. Future Microbiol. 2014;9(6):791–805. doi:10.2217/fmb.14.32

29.

Wohlleben

Mast

Stegmann

Ziemert

. Antibiotic drug discovery. Microb Biotechnol. 2016;9(5):541–548. doi:10.1111/1751-7915.12388

30.

Zhu

Qin

, et al. Drug discovery prospect from untapped species: indications from approved natural product drugs. PLoS One. 2012;7(7):e39782. doi:10.1371/journal.pone.0039782

31.

Zhu

Qin

Tao

, et al. Clustered patterns of species origins of nature-derived drugs and clues for future bioprospecting. Proc Natl Acad Sci USA. 2011;108(31):12943–12948. doi:10.1073/pnas.1107336108

32.

Cordell

. Biodiversity and drug discovery - a symbiotic relationship. Phytochemistry. 2000;55(6):463–480. doi:10.1016/S0031-9422(00)00230-2

33.

Tulp

Bohlin

. Functional versus chemical diversity: is biodiversity important for drug discovery? Trends Pharmacol Sci. 2002;23(5):225–231. doi:10.1016/S0165-6147(02)02007-2

34.

Lefevre

Robe

Jarrin

, et al. Drugs from hidden bugs: their discovery via untapped resources. Res Microbiol. 2008;159(3):153–161. doi:10.1016/j.resmic.2007.12.011

35.

Springer

Buchi

Kobbe

Demain

Clardy

. The structure of ditryptophenaline - a new metabolite of Aspergillus flavus. Tetrahedron Lett. 1977;18(28):2403–2406. doi:10.1016/S0040-4039(01)83777-1

36.

Abd El-Rahman

TMA

Tharwat

Abo El-Souad

SMS

El-Beih

El-Diwany

. Biological activities and variation of symbiotic fungi isolated from coral reefs collected from red sea in Egypt. Mycology. 2020;11(3):243–255. doi:10.1080/21501203.2020.1741470

37.

Hawas

El-Beih

El-Halawany

. Bioactive anthraquinones from endophytic fungus Aspergillus versicolor isolated from red sea algae. Arch Pharm Res. 2012;35(10):1749–1756. doi:10.1007/s12272-012-1006-x

38.

Hawas

Al-Farawati

El-Kassem

LTA

Turki

. Different culture metabolites of the red sea fungus Fusarium equiseti optimize the inhibition of hepatitis C virus NS3/4A protease (HCV PR). Mar Drugs. 2016;14(10):190. doi:10.3390/md14100190

39.

Asiri

IAM

Badr

Youssef

DTA

. Penicillivinacine, antimigratory diketopiperazine alkaloid from the marine-derived fungus Penicillium vinaceum. Phytochem Lett. 2015;13(423):53–58. doi:10.1016/j.phytol.2015.05.014

40.

Shaala

Youssef

DTA

. Identification and bioactivity of compounds from the fungus Penicillium sp. CYE-87 isolated from a marine tunicate. Mar Drugs. 2015;13(4):1698–1709. doi:10.3390/md13041698

41.

Mourshid

SSA

Badr

Risinger

Mooberry

Youssef

DTA

. Penicilloitins A and B, new antimicrobial fatty acid esters from a marine endophytic Penicillium species. Zeitschrift fur Naturforschung C. 2016;71(11-12):387–392. doi:10.1515/znc-2015-0242

42.

Atalla

Zeinab

Eman

Amani

Abeer

AAEA

. Production of some biologically active secondary metabolites from marine-derived fungus Varicosporina ramulosa. Malays J Microbiol. 2008;4(1):14–24. doi:10.21161/mjm.01608

43.

Panizel

Yarden

Ilan

Carmeli

. Eight new peptaibols from sponge-associated Trichoderma atroviride. Mar Drugs. 2013;11(12):4937–4960. doi:10.3390/md11124937

44.

Cohen

Koch

Thu

, et al. Novel terpenoids of the fungus Aspergillus insuetus isolated from the Mediterranean sponge Psammocinia sp. Collected along the coast of Israel. Bioorg Med Chem. 2011;19(22):6587–6593. doi:10.1016/j.bmc.2011.05.045

45.

Koch

Lodin

Herold

Ilan

Carmeli

Yarden

. Sensitivity of Neurospora crassa to a marine-derived Aspergillus tubingensis anhydride exhibiting antifungal activity that is mediated by the MAS1 protein. Mar Drugs. 2014;12(9):4713–4731. doi:10.3390/md12094713

46.

Liarzi

Bar

Lewinsohn

Ezra

. Use of the endophytic fungus Daldinia cf. concentrica and its volatiles as bio-control agents. PLoS One. 2016;11(12):e0168242. doi:10.1371/journal.pone.0168242

47.

Noumeur

Helaly

Jansen

, et al. Preussilides A-F, bicyclic polyketides from the endophytic fungus Preussia similis with antiproliferative activity. J Nat Prod. 2017;80(5):1531–1540. doi:10.1021/acs.jnatprod.7b00064

48.

Chowdhury

Hasan

Rashid

. Antimicrobial activity of Toona ciliata and Amoora rohituka. Fitoterapia. 2003;74(1-2):155–158. doi:10.1016/S0367-326X(02)00322-2

49.

Cunningham

Manson

Spring

Hutchinson

. Cordycepin, a metabolic product isolated from cultures of Cordyceps militaris (linn.) link. Nature. 1950;166(4231):949–949. doi:10.1038/166949a0

50.

Kiyoto

Kawai

Kawakita

, et al. A new antitumor complex, WF-1360, WF-1360A, B, C, D, E and F. J Antibiot (Tokyo). 1986;39(6):762–772. doi:10.7164/antibiotics.39.762

51.

Hawas

El-Halawany

Ahmed

. Hepatitis C virus NS3-NS4A protease inhibitors from the endophytic Penicillium chrysogenum isolated from the red alga Liagora viscida. Zeitschrift fur Naturforschung C. 2013;68(9-10):355–366. doi:10.1515/znc-2013-9-1003

52.

Grundmann

. Overproduction, purification and characterization of FtmPT1, a brevianamide F prenyltransferase from Aspergillus fumigatus. Microbiology (Reading). 2005;151(7):2199–2207. doi:10.1099/mic.0.27962-0

53.

Larsen

Breinholt

. Dichlorodiaportin, diaportinol, and diaportinic acid: three novel isocoumarins from Penicillium nalgiovense. J Nat Prod. 1999;62(8):1182–1184. doi:10.1021/np990066b

54.

Lin

Fang

, et al. Iso-α-cyclopiazonic acid, a new natural product isolated from the marine-derived fungus Aspergillus flavus C-F-3. Chem Nat Compd. 2009;45(5):677–680. doi:10.1007/s10600-009-9433-8

55.

Shen

Zou

Xie

Cao

Dai

. Butyrolactone and cycloheptanetrione from mangrove-associated fungus Aspergillus terreus. Chem Pharm Bull (Tokyo). 2012;60(11):1437–1441. doi:10.1248/cpb.c12-00616

56.

Shiono

Hiramatsu

Murayama

, et al. Two drimane-type sesquiterpenes, strobilactones A and B, from the liquid culture of the edible mushroom Strobilurus ohshimae. Z. Naturforsch. 2007;62b(9):1585–1589. doi:0932–0776/07/1200–1585

57.

Indraningrat

AAG

Smidt

Sipkema

. Bioprospecting sponge-associated microbes for antimicrobial compounds. Mar Drugs. 2016;14(5):87. doi:10.3390/md14050087

58.

Weidenmüller

Cavagna

Fehlhaber

Präve

. 2-Carboxymethyl-3-n-hexyl-maleic acid anhydride, a novel metabolite from an Aspergillus. Tetrahedron Lett. 1972;13(33):3519–3522. doi:10.1016/S0040-4039(01)94088-2

59.

Bisignano

LaganÃ

Trombetta

, et al. In vitro antibacterial activity of some aliphatic aldehydes from Olea europaea L. FEMS Microbiol Lett. 2001;198(1):9–13. doi:10.1111/j.1574-6968.2001.tb10611.x

60.

Groenhagen

Baumgartner

Bailly

, et al. Production of bioactive volatiles by different Burkholderia ambifaria strains. J Chem Ecol. 2013;39(10):1343–1345. doi:10.1007/s10886-013-0346-4

61.

Euch IZ

Frese

Sewald

Smaoui

Shaaban

Mellouli

. Bioactive secondary metabolites from new terrestrial Streptomyces sp. TN82 strain: isolation, structure elucidation and biological activity. Med Chem Res. 2018;27(4):1085–1092. doi:10.1007/s00044-017-2130-4

62.

Smaoui

Mathieu

Elleuch

, et al. Taxonomy, purification and chemical characterization of four bioactive compounds from new Streptomyces sp. TN256 strain. World J Microbiol Biotechnol. 2012;28(3):793–804. doi:10.1007/s11274-011-0872-6

63.

Saadouli

el Euch

Trabelsi

, et al. Isolation, characterization and chemical synthesis of large spectrum antimicrobial cyclic dipeptide (L-leu-L-pro) from Streptomyces misionensis V16R3Y1 bacteria extracts. A novel 1H NMR metabolomic approach. Antibiotics. 2020;9(5):270. doi:10.3390/antibiotics9050270

64.

Elleuch

Shaaban

Smaoui

, et al. Bioactive secondary metabolites from a new terrestrial Streptomyces sp. TN262. Appl Biochem Biotechnol. 2010;162(2):579–593. doi:10.1007/s12010-009-8808-4

65.

Khebizi

Boudjella

Bijani

, et al. Oligomycins A and E, major bioactive secondary metabolites produced by Streptomyces sp. Strain HG29 isolated from a saharan soil. J Mycol Med. 2018;28(1):150–160. doi:10.1016/j.mycmed.2017.10.007

66.

Hadj Rabia-Boukhalfa

Eveno

Karama

, et al. Isolation, purification and chemical characterization of a new angucyclinone compound produced by a new halotolerant Nocardiopsis sp. HR-4 strain. World J Microbiol Biotechnol. 2017;33(6):126. doi:10.1007/s11274-017-2292-8

67.

El-Naggar

El-Assar

Abdul-Gawad

. Meroparamycin production by newly isolated Streptomyces sp. Strain MAR01: taxonomy, fermentation, purification and structural elucidation. J Microbiol. 2006;44(4):432–438.

68.

Yassien

Abdallah

El-Halawany

Jiman-Fatani

AAM

. Anti-tuberculous activity of treponemycin produced by a Streptomyces strain MS-6-6 isolated from Saudi Arabia. Molecules. 2015;20(2):2576–2590. doi:10.3390/molecules20022576

69.

Mussa

Abdulkareem

Kareem

MKA

. Antimicrobial activity of novel peptide compound produced by Bacillus licheniformis isolated from Iraqi soil on UTI bacteria. Plant Arch. 2020;20(1):2447–2453.

70.

Ugras

Sezen

Kati

Demirbag

. Purification and characterization of the bacteriocin thuricin Bn1 produced by Bacillus thuringiensis subsp. kurstaki Bn1 isolated from a hazelnut pest. J Microbiol Biotechnol. 2013;23(2):167–176. doi:10.4014/jmb.1209.09056

71.

Norouzi

Khorasgani

Danesh

. Anti-MRSA activity of a bioactive compound produced by a marine Streptomyces and its optimization using statistical experimental design. Iran J Basic Med Sci. 2019;22(9):1073–1084. doi:10.22038/IJBMS.2019.33880.8058

72.

Gozari

Bahador

Mortazavi

Eftekhar

Jassbi

. An “olivomycin A” derivative from a sponge-associated Streptomyces sp. Strain SP 85. 3 Biotech. 2019;9(12):439. doi:10.1007/s13205-019-1964-5

73.

Karbalaei-Heidari

Partovifar

Memarpoor-Yazdi

. Evaluation of the bioactive potential of secondary metabolites produced by a new marine Micrococcus species isolated from the Persian gulf. Avicenna J Med Biotechnol. 2020;12(1):61–65.

74.

Matroodi

Siitonen

Baral

Yamada

Akhgari

Metsä-Ketelä

. Genotyping-guided discovery of persiamycin A from sponge-associated halophilic Streptomonospora sp. PA3. Front Microbiol. 2020;11(7):1237. doi:10.3389/fmicb.2020.01237

75.

Almalki

. Isolation and characterization of polyketide drug molecule from Streptomyces species with antimicrobial activity against clinical pathogens. J Infect Public Health. 2020;13(1):125–130. doi:10.1016/j.jiph.2019.07.002

76.

Wang

Gui

, et al. Identification, bioactivity, and productivity of actinomycins from the marine-derived Streptomyces heliomycini. Front Microbiol. 2017;8(29):1147. doi:10.3389/fmicb.2017.01147

77.

Shaala

Youssef

DTA

Alzughaibi

Elhady

. Antimicrobial chlorinated 3-phenylpropanoic acid derivatives from the red sea marine actinomycete Streptomyces coelicolor LY001. Mar Drugs. 2020;18(9):450. doi:10.3390/md18090450

78.

Shaala

Youssef

DTA

McPhail

Elbandy

. Malyngamide 4, a new lipopeptide from the red sea marine cyanobacterium Moorea producens (formerly Lyngbya majuscula). Phytochem Lett. 2013;6(2):183–188. doi:10.1016/j.phytol.2013.01.002

79.

Fathoni

Petitbois

Alarif

, et al. Bioactivities of lyngbyabellins from cyanobacteria of Moorea and Okeania genera. Molecules. 2020;25(17):3986. doi:10.3390/molecules25173986

80.

Fotso Fondja Yao

Al Zereini

Fotso

Anke

Laatsch

. Aqabamycins A-G: novel nitro maleimides from a marine Vibrio species: iI. Structure elucidation. J Antibiot (Tokyo). 2010;63(6):303–308. doi:10.1038/ja.2010.35

81.

Al-Zereini

Fotso Fondja Yao

Laatsch

Anke

. Aqabamycins A-G: novel nitro maleimides from a marine Vibrio species. I. Taxonomy, fermentation, isolation and biological activities. J Antibiot (Tokyo). 2010;63(6):297–301. doi:10.1038/ja.2010.34

82.

Abdelmohsen

Cheng

Viegelmann

, et al. Dereplication strategies for targeted isolation of new antitrypanosomal actinosporins A and B from a marine sponge associated-Actinokineospora sp. EG49. Mar Drugs. 2014;12(3):1220–1244. doi:10.3390/md12031220

83.

Tawfike

Attia

Desoukey

, et al. New bioactive metabolites from the elicited marine sponge-derived bacterium Actinokineospora spheciospongiae sp. Nov. AMB Express. 2019;9(1):12. doi:10.1186/s13568-018-0730-0

84.

Hifnawy

Hassan

Mohammed

, et al. Induction of antibacterial metabolites by co-cultivation of two red-sea-sponge-associated actinomycetes Micromonospora sp. UR56 and Actinokinespora sp. EG49. Mar Drugs. 2020;18(5):243. doi:10.3390/md18050243

85.

El-Gendy

MMA

El-Bondkly

AMA

. Production and genetic improvement of a novel antimycotic agent, saadamycin, against dermatophytes and other clinical fungi from endophytic Streptomyces sp. Hedaya48. J Ind Microbiol Biotechnol. 2010;37(8):831–841. doi:10.1007/s10295-010-0729-2

86.

Alzahrani

El-Bondkly

AAM

El-Gendy

MMAA

El-Bondkly

. Enhancement of undecylprodigiosin production from marine endophytic recombinant strain Streptomyces sp. ALAA-R20 through low-cost induction strategy. J Appl Genet. 2021;62(1):165–182. doi:10.1007/s13353-020-00597-x

87.

El-Gendy

MMA

Hawas

Jaspars

. Novel bioactive metabolites from a marine derived bacterium Nocardia sp. ALAA 2000. J Antibiot (Tokyo). 2008;61(6):379–386. doi:10.1038/ja.2008.53

88.

El-Gendy

MMA

Shaaban

El-Bondkly

Laatsch

. Essramycin: a first triazolopyrimidine antibiotic isolated from nature. J Antibiot (Tokyo). 2008;61(3):149–157. doi:10.1038/ja.2008.124

89.

Kim

Cullum

Hebishy

AMS

, et al. Mersaquinone, a new tetracene derivative from the marine-derived Streptomyces sp. Eg1 exhibiting activity against methicillin-resistant Staphylococcus aureus (MRSA). Antibiotics. 2020;9(5):252. doi:10.3390/antibiotics9050252

90.

El-Gendy

MMA

Shaaban

El-Bondkly

Shaaban

. Bioactive benzopyrone derivatives from new recombinant fusant of marine Streptomyces. Appl Biochem Biotechnol. 2008;150(1):85–96. doi:10.1007/s12010-008-8192-5

91.

Djinni

Defant

Kecha

Mancini

. Antibacterial polyketides from the marine alga-derived endophitic Streptomyces sundarbansensis: a study on hydroxypyrone tautomerism. Mar Drugs. 2013;11(1):124–135. doi:10.3390/md11010124

92.

Djinni

Defant

Kecha

Mancini

. Metabolite profile of marine-derived endophytic Streptomyces sundarbansensis WR1L1S8 by liquid chromatography-mass spectrometry and evaluation of culture conditions on antibacterial activity and mycelial growth. J Appl Microbiol. 2014;116(1):39–50. doi:10.1111/jam.12360

93.

Khan

Yılmaz

Aksoy

, et al. Polyethers isolated from the marine actinobacterium Streptomyces cacaoi inhibit autophagy and induce apoptosis in cancer cells. Chem Biol Interact. 2019;307(4--6):167–178. doi:10.1016/j.cbi.2019.04.035

94.

Dashti

Grkovic

Abdelmohsen

Hentschel

Quinn

. Production of induced secondary metabolites by a co-culture of sponge-associated actinomycetes, Actinokineospora sp. EG49 and Nocardiopsis sp. RV163. Mar Drugs. 2014;12(5):3046–3059. doi:10.3390/md12053046

95.

Hodge

Harris

. Verrucofortine, a major metabolite of Penicillium verrucosum var. Cyclopium, the fungus that produces the mycotoxin verrucosidin. J Nat Prod. 1988;51(1):66–73. doi:10.1021/np50055a008

96.

Yassa

Masoomi

Rohani Rankouhi

Hadjiakhoondi

. Chemical composition and antioxidant activity of the extract and essential oil of Rosa damascena from Iran, population of guilan. Daru. 2009;17(3):175–180.

97.

Krastel

Zeeck

Gebhardt

Fiedler

Rheinheimer

. Endophenazines A-D, new phenazine antibiotics from the athropod associated endosymbiont Streptomyces anulatus. II. Structure elucidation. J Antibiot (Tokyo). 2002;55(9):801–806. doi:10.7164/antibiotics.55.801

98.

Lee

Kim

Lim

Kim

. Anti-leukaemic and anti-mutagenic effects of di(2-ethylhexyl)phthalate isolated from Aloe vera linne. J Pharm Pharmacol. 2000;52(5):593–598. doi:10.1211/0022357001774246

99.

Arunrattiyakorn

Nitoda

Kanzaki

. Enzymatic conversion-based method for screening cyclic dipeptide-producing microbes. Peptides. 2006;27(4):633–639. doi:10.1016/j.peptides.2005.08.017

100.

Kumar S

Mohandas

Siji J

Rajasekharan

Nambisan

. Identification of antimicrobial compound, diketopiperazines, from a Bacillus sp. N strain associated with a rhabditid entomopathogenic nematode against major plant pathogenic fungi. J Appl Microbiol. 2012;113(4):914–924. doi:10.1111/j.1365-2672.2012.05385.x

101.

Schiewe

Zeeck

. Cineromycins, γ-butyrolactones and ansamycins by analysis of the secondary metabolite pattern created by a single strain of Streptomyces. J Antibiot (Tokyo). 1999;52(7):635–642. doi:10.7164/antibiotics.52.635

102.

Erdogan

Şener

Higa

. Tryptophol, a plant auxin isolated from the marine sponge Ircinia spinulosa. Biochem Syst Ecol. 2000;28(8):793–794. doi:10.1016/S0305-1978(99)00111-8

103.

Carter

. Structure determination of oligomycins A and C. J Org Chem. 1986;51(22):4264–4271. doi:10.1021/jo00372a030

104.

Kobayashi

Nishino

Ohya

, et al. Oligomycin E, a new antitumor antibiotic produced by Streptomyces sp. McI-2225. J Antibiot (Tokyo). 1987;40(7):1053–1057. doi:10.7164/antibiotics.40.1053

105.

Kesenheimer

Kalogerakis

Meißner

Groth

. The cobalt way to angucyclinones: asymmetric total synthesis of the antibiotics ( + )-rubiginone B2, (-)-tetrangomycin, and (-) −8-O-methyltetrangomycin. Chemistry. 2010;16(29):8805–8821. doi:10.1002/chem.201000804

106.

Singh

Gurusiddaiah

Whalen

. Treponemycin, a nitrile antibiotic active against Treponema hyodysenteriae. Antimicrob Agents Chemother. 1985;27(2):239–245. doi:10.1128/AAC.27.2.239

107.

Singh

Genilloud

Peláez

. Terrestrial microorganisms - filamentous bacteria. In: Lew M, Hung-wen L, eds. Comprehensive Natural Products II: Chemistry and Biology, Vol 2. Elsevier Ltd; 2010:109–140.

108.

Diegelmann

Katz

Mauger

. Isolation and identification of oxoproline in actinomycin X2 (V) hydrolysates. J Antibiot (Tokyo). 1969;22(2):85–87. doi:10.7164/antibiotics.22.85

109.

Cho

Goo

Kim

. Identification of actinomycins by high performance liquid chromatography and fast atom bombardment mass spectrometry. Arch Pharm Res. 1994;17(6):424–427. doi:10.1007/BF02979119

110.

Wang

Yang

, et al. Acaricidal activity of cyclodipeptides from Bacillus amyloliquefaciens W1 against Tetranychus urticae. J Agric Food Chem. 2018;66(39):10163–10168. doi:10.1021/acs.jafc.8b03806

111.

De Rosa

Mitova

Tommonaro

. Marine bacteria associated with sponge as source of cyclic peptides. In: Wijffels RH, Barbosa M, Janssen M, et al. eds. Biomolecular Engineering, Vol 20. Elsevier; 2003:311–316. doi:10.1016/S1389-0344(03)00038-8

112.

Cardellina

Dalietos

Marner

Mynderse

Moore

. (-)-Trans-7(S)-methoxytetradec-4-enoic acid and related amides from the marine cyanophyte Lyngbya majuscula. Phytochemistry. 1978;17(12):2091–2095. doi:10.1016/S0031-9422(00)89287-0

113.

Petitbois

Casalme

Lopez

, et al. Serinolamides and lyngbyabellins from an Okeania sp. Cyanobacterium collected from the red sea. J Nat Prod. 2017;80(10):2708–2715. doi:10.1021/acs.jnatprod.7b00449

114.

Messenger

AJM

Turner

. Phenazine-1,6-dicarboxylate and its dimethyl ester as precursors of other phenazines in bacteria. FEMS Microbiol Lett. 1983;18(1-2):65–68. doi:10.1111/j.1574-6968.1983.tb00450.x

115.

Tanaka

. Phenomycin and enomycin. In: Hahn

, ed. Mechanism of Action of Antibacterial Agents. Antibiotics, Vol 5. Springer Berlin Heidelberg; 1979:235–242.

116.

National Center for Biotechnology Information. PubChem compound summary for CID 76959, 4-methoxybenzamide. Published 2021. Accessed February 21, 2021. https://pubchem.ncbi.nlm.nih.gov/compound/4-Methoxybenzamide

117.

Meschke

Walter

Schrempf

. Characterization and localization of prodiginines from Streptomyces lividans suppressing Verticillium dahliae in the absence or presence of Arabidopsis thaliana. Environ Microbiol. 2012;14(4):940–952. doi:10.1111/j.1462-2920.2011.02665.x

118.

El-Seedi

. Antimicrobial arylcoumarins from Asphodelus microcarpus. J Nat Prod. 2007;70(1):118–120. doi:10.1021/np060444u

119.

Shi

Zhang

. Constituents of Eremurus chinensis. J Nat Prod. 2000;63(5):653–656. doi:10.1021/np9904915

120.

Nukul

Abu Zarga

Sabri

Al-Eisawi

. Chemical constituents of the flora of Jordan, part III: 1Mono-o-acetyl diphyllin apioside, a new arylnaphthalene lignan from Haplophyllum buxbaumii. J Nat Prod. 1987;50(4):748–750. doi:10.1021/np50052a032

121.

Wang

Hesek

Lee

, et al. The natural product essramycin and three of its isomers are devoid of antibacterial activity. J Nat Prod. 2016;79(4):1219–1222. doi:10.1021/acs.jnatprod.6b00057

122.

Cheng

Jensen

Fenical

. Arenaric acid, a new pentacyclic polyether produced by a marine bacterium (actinomycetales). J Nat Prod. 1999;62(4):605–607. doi:10.1021/np9801357

123.

Tsuji

Nagashima

Kobayashi

Wakisaka

Kawamura

Kōzuki

. Two new antibiotics, A-218 and K-41 isolation and characterization. J Antibiot (Tokyo). 1976;29(1):10–14. doi:10.7164/antibiotics.29.10

124.

Mahapatra

Raman

Nayak

Gouda

Das

Patra

. Metagenomics approaches in discovery and development of new bioactive compounds from marine Actinomycetes. Curr Microbiol. 2020;77(4):645–656. doi:10.1007/s00284-019-01698-5

125.

Schloss

Handelsman

. Biotechnological prospects from metagenomics. Curr Opin Biotechnol. 2003;14(3):303–310. doi:10.1016/S0958-1669(03)00067-3

126.

Qin

. Metagenomics-based drug discovery and marine microbial diversity. Trends Biotechnol. 2005;23(11):539–543. doi:10.1016/j.tibtech.2005.08.006

127.

da Cunha

Fonseca

Calado

CRC

. Antibiotic discovery: where have we come from, where do we go? Antibiotics. 2019;8(2):45. doi:10.3390/antibiotics8020045

128.

Gillespie

Brady

Bettermann

, et al. Isolation of antibiotics turbomycin A and B from a metagenomic library of soil microbial DNA. Appl Environ Microbiol. 2002;68(9):4301–4306. doi:10.1128/AEM.68.9.4301-4306.2002

129.

Brady

Chao

Clardy

. New natural product families from an environmental DNA (eDNA) gene cluster. J Am Chem Soc. 2002;124(34):9968–9969. doi:10.1021/ja0268985

130.

Brady

Chao

Handelsman

Clardy

. Cloning and heterologous expression of a natural product biosynthetic gene cluster from eDNA. Org Lett. 2001;3(13):1981–1983. doi:10.1021/ol015949k

131.

Piel

. A polyketide synthase-peptide synthetase gene cluster from an uncultured bacterial symbiont of Paederus beetles. Proc Natl Acad Sci USA. 2002;99(22):14002–14007. doi:10.1073/pnas.222481399

132.

Mitchell

Scheremetjew

Denise

, et al. EBI Metagenomics in 2017: enriching the analysis of microbial communities, from sequence reads to assemblies. Nucleic Acids Res. 2018;46(D1):D726–D735. doi:10.1093/nar/gkx967

133.

. Metagenomics: aid to combat antimicrobial resistance in diarrhea. Gut Pathog. 2019;11(D1):47. doi:10.1186/s13099-019-0331-8

134.

Mishra

Ganju

Sairam

Banerjee

Sawhney

. A review of high throughput technology for the screening of natural products. Biomed Pharmacother. 2008;62(2):94–98. doi:10.1016/j.biopha.2007.06.012

135.

Avery

Camp

Carroll

Jenkins

Quinn

. The identification of bioactive natural products by high throughput screening (HTS). In: Lew M, Hung-wen L, eds. Comprehensive Natural Products II: Chemistry and Biology. Elsevier Sciences; 2010;(2):177–203.

136.

Paytubi

de La Cruz

Tormo

, et al. A high-throughput screening platform of microbial natural products for the discovery of molecules with antibiofilm properties against Salmonella. Front Microbiol. 2017;8:326. doi:10.3389/fmicb.2017.00326

137.

Itoh

Tokumoto

Kaji

, et al. Development of a high-throughput strategy for discovery of potent analogues of antibiotic lysocin E. Nat Commun. 2019;10(1):2992. doi:10.1038/s41467-019-10754-4

138.

Dorr

Westby

Dobbs

, et al. Maraviroc (UK-427,857), a potent, orally bioavailable, and selective small-molecule inhibitor of chemokine receptor CCR5 with broad-spectrum anti-human immunodeficiency virus type 1 activity. Antimicrob Agents Chemother. 2005;49(11):4721–4732. doi:10.1128/AAC.49.11.4721-4732.2005

139.

Szymański

Markowicz

Mikiciuk-Olasik

. Adaptation of high-throughput screening in drug discovery-toxicological screening tests. Int J Mol Sci. 2012;13(1):427–452. doi:10.3390/ijms13010427

140.

Carnero

. High throughput screening in drug discovery. Clin Transl Oncol. 2006;8(7):482–490. doi:10.1007/s12094-006-0048-2

141.

Martis

Radhakrishnan

Badve

. High-throughput screening: the hits and leads of drug discovery-an overview. J Appl Pharm Sci. 2011;1(1):2–10.

142.

Ruge

Korting

Borelli

. Current state of three-dimensional characterisation of antifungal targets and its use for molecular modelling in drug design. Int J Antimicrob Agents. 2005;26(6):427–441. doi:10.1016/j.ijantimicag.2005.09.006

143.

Patel

Kukol

. Integrating molecular modelling methods to advance influenza A virus drug discovery. Drug Discov Today. 2021;26(2):503–510. doi:10.1016/j.drudis.2020.11.014

144.

Jorgensen

. The many roles of computation in drug discovery. Science. 2004;303(5665):1813–1818. doi:10.1126/science.1096361

145.

Wang

Yang

Gao

Niu

. Discovery of the novel inhibitor against New Delhi metallo-β-lactamase based on virtual screening and molecular modelling. Int J Mol Sci. 2020;21(10):3567. doi:10.3390/ijms21103567

146.

Narayanan

Velmurugan

. Molecular modeling studies and ADME screening on HIV-1 integrase inhibitors as anti-viral agents. Int J Sci. 2013;2(05):1–12.

147.

Barril

Soliva

. Molecular modelling. Mol Biosyst. 2006;2(12):660–681. doi:10.1039/B613461K

Antimicrobial Natural Products Derived from Microorganisms Inhabiting the MENA Region

Abstract

Objective/Background

Methods

Results

Conclusion

Keywords

Introduction

Pure Compounds

Fungi

Bacteria

Terrestrial Bacteria

Marine Bacteria

Geological Distribution of Antimicrobial NPs in the MENA Region

Methods to Improve the Discovery of Antimicrobial NPs in the MENA Region

Metagenomics

High-Throughput Screening

Molecular Modeling

Conclusion

Footnotes

Acknowledgements

Declaration of Conflicting Interests

Funding

ORCID iD

References