Mycobacterium spp. intimidated mankind since time immemorial. The triumph over this organism was anticipated with the introduction of potent antimicrobials in the mid-20th century. However, the emergence of drug resistance in mycobacteria, Mycobacterium tuberculosis, in particular, caused great concern for the treatment. With the enemy growing stronger, there is an immediate need to equip the therapeutic arsenal with novel and potent chemotherapeutic agents. The task seems intricating as our understanding of the dynamic nature of the mycobacteria requires intense experimentation and research. Targeting the mycobacterial cell envelope appears promising, but its versatility allows it to escape the lethal effect of the molecules acting on it. The unique ability of hiding (inactivity during latency) also assists the bacterium to survive in a drug-rich environment. The drug delivery systems also require upgradation to allow better bioavailability and tolerance in patients. Although the resistance to the novel drugs is inevitable, our commitment to the research in this area will ensure the discovery of effective weapons against this formidable opponent.
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References
1.
World Health Organization. Global Tuberculosis Report 2021. World Health Organization: Geneva; 2021.
2.
McQuaidCF, VassallA, CohenT, et al.The impact of COVID-19 on TB: A review of the data. Int J Tuberc Lung Dis, 2021; 25(6):436–446.
3.
World Health Organization. Tuberculosis Key Facts. World Health Organization: Geneva; 2021.
4.
LiuY, MatsumotoM, IshidaH, et al.Delamanid: From discovery to its use for pulmonary multidrug-resistant tuberculosis (MDR-TB). Tuberculosis (Edinb), 2018; 111:20–30.
5.
GuptaA, KumarV, NatarajanS, et al.Adverse drug reactions & drug interactions in MDR-TB patients. Indian J Tuberc, 2020; 67(4S):S69–S78.
6.
GopalanN, ChandrasekaranP, SwaminathanS, et al.Current trends and intricacies in the management of HIV-associated pulmonary tuberculosis. AIDS Res Ther, 2016; 13:34.
7.
KonyarikováZ, SavkováK, KozmonS, et al.Biosynthesis of galactan in Mycobacterium tuberculosis as a viable TB drug target?. Antibiotics (Basel), 2020; 9(1):20.
8.
BhatZS, RatherMA, MaqboolM, et al.Cell wall: A versatile fountain of drug targets in Mycobacterium tuberculosis. Biomed Pharmacother, 2017; 95:1520–1534.
Bansal-MutalikR, NikaidoH. Mycobacterial outer membrane is a lipid bilayer and the inner membrane is unusually rich in diacyl phosphatidylinositol dimannosides. Proc Natl Acad Sci U S A, 2014; 111(13):4958–4963.
ChakrabortyS, RheeKY. Tuberculosis drug development: History and evolution of the mechanism-based paradigm. Cold Spring Harb Perspect Med, 2015; 5(8):a021147.
16.
TimminsGS, DereticV. Mechanisms of action of isoniazid. Mol Microbiol, 2006; 62(5):1220–1227.
17.
SomoskoviA, ParsonsLM, SalfingerM. The molecular basis of resistance to isoniazid, rifampin, and pyrazinamide in Mycobacterium tuberculosis. Respir Res, 2001; 2(3):164–168.
18.
SulisG, PaiM. Isoniazid-resistant tuberculosis: A problem we can no longer ignore. PLoS Med, 2020; 17(1):e1003023.
19.
UnissaAN, SubbianS, HannaLE, et al.Overview on mechanisms of isoniazid action and resistance in Mycobacterium tuberculosis. Infect Genet Evol, 2016; 45:474–492.
20.
GhodousiA, TaglianiE, KarunaratneE, et al.Isoniazid resistance in Mycobacterium tuberculosis is a heterogeneous phenotype composed of overlapping MIC distributions with different underlying resistance mechanisms. Antimicrob Agents Chemother, 2019; 63(7):e00092-19.
21.
ArunKB, MadhavanA, AbrahamB, et al.Acetylation of isoniazid is a novel mechanism of isoniazid resistance in Mycobacterium tuberculosis. Antimicrob Agents Chemother, 2020; 65(1):e00456-20.
AngMLT, Zainul RahimSZ, de SessionsPF, et al.EthA/R-independent killing of Mycobacterium tuberculosis by ethionamide. Front Microbiol, 2017; 8:710.
24.
ValeN, GomesP, SantosHA. Metabolism of the antituberculosis drug ethionamide. Curr Drug Metab, 2013; 14(1):151–158.
25.
WolffKA, NguyenL. Strategies for potentiation of ethionamide and folate antagonists against Mycobacterium tuberculosis. Expert Rev Anti Infect Ther, 2012; 10(9):971–981.
26.
LabordeJ, DeraeveC, DuhayonC, et al.Ethionamide biomimetic activation and an unprecedented mechanism for its conversion into active and non-active metabolites. Org Biomol Chem, 2016; 14(37):8848–8858.
27.
DeshpandeD, PasipanodyaJG, MpagamaSG, et al.Ethionamide pharmacokinetics/pharmacodynamics-derived dose, the role of MICs in clinical outcome, and the resistance arrow of time in multidrug-resistant tuberculosis. Clin Infect Dis, 2018; 67(Suppl 3):S317–S326.
28.
Hok TT. A comparative study of the susceptibility to ethionamide, thiosemicarbazone, and isoniazid of tubercle bacilli from patients never treated with ethionamide or thiosemicarbazone. Am Rev Respir Dis, 1964; 90:468–469.
29.
SreevatsanS, StockbauerKE, PanX, et al.Ethambutol resistance in Mycobacterium tuberculosis: Critical role of embB mutations. Antimicrob Agents Chemother, 1997; 41(8):1677–1681.
30.
LiMC, ChenR, LinSQ, et al.Detecting ethambutol resistance in Mycobacterium tuberculosis isolates in China: A comparison between phenotypic drug susceptibility testing methods and DNA sequencing of embAB. Front Microbiol, 2020; 11:781.
31.
PawarA, JhaP, ChopraM, et al.Screening of natural compounds that targets glutamate racemase of Mycobacterium tuberculosis reveals the anti-tubercular potential of flavonoids. Sci Rep, 2020; 10(1):949.
32.
SafiH, LingarajuS, AminA, et al.Evolution of high-level ethambutol-resistant tuberculosis through interacting mutations in decaprenylphosphoryl-β-D-arabinose biosynthetic and utilization pathway genes. Nat Genet, 2013; 45(10):1190–1197.
33.
Kahana LM. Toxic ocular effects of ethambutol. CMAJ 1987;137(3):213–216. Erratum in: Can Med Assoc J, 1987; 137(7):592.
34.
Leibold JE. The ocular toxicity of ethambutol and its relation to dose. Ann N Y Acad Sci, 1966; 135(2):904–909.
35.
AlghamdiWA, AlsultanA, Al-ShaerMH, et al.Cycloserine population pharmacokinetics and pharmacodynamics in patients with tuberculosis. Antimicrob Agents Chemother, 2019; 63(5):e00055-19.
36.
YuX, ZengX, ShiW, et al.Validation of cycloserine efficacy in treatment of multidrug-resistant and extensively drug-resistant tuberculosis in Beijing, China. Antimicrob Agents Chemother, 2018; 62(3):e01824-17.
37.
ChenJ, ZhangS, CuiP, et al.Identification of novel mutations associated with cycloserine resistance in Mycobacterium tuberculosis. J Antimicrob Chemother, 2017; 72(12):3272–3276.
38.
MiglioriGB, PontaliE, SotgiuG, et al.Combined use of delamanid and bedaquiline to treat multidrug-resistant and extensively drug-resistant tuberculosis: A systematic review. Int J Mol Sci, 2017; 18(2):341.
39.
MuddeSE, UptonAM, LenaertsA, et al.Delamanid or pretomanid?. A Solomonic judgement! J Antimicrob Chemother, 2022; 77(4):880–902.
40.
HayashiM, NishiyamaA, KitamotoR, et al.Adduct formation of delamanid with NAD in mycobacteria. Antimicrob Agents Chemother, 2020; 64(5):e01755-19.
41.
LiY, SunF, ZhangW. Bedaquiline and delamanid in the treatment of multidrug-resistant tuberculosis: Promising but challenging. Drug Dev Res, 2019; 80(1):98–105.
42.
ThakareR, DasguptaA, ChopraS. Pretomanid for the treatment of pulmonary tuberculosis. Drugs Today (Barc), 2020; 56(10):655–668.
43.
ConradieF, DiaconAH, NgubaneN, et al.Treatment of highly drug-resistant pulmonary tuberculosis. N Engl J Med, 2020; 382(10):893–902.
44.
KanaBD, KarakousisPC, ParishT, et al.Future target-based drug discovery for tuberculosis?. Tuberculosis (Edinb), 2014; 94(6):551–556.
45.
SloanDJ, DaviesGR, KhooSH. Recent advances in tuberculosis: New drugs and treatment regimens. Curr Respir Med Rev, 2013; 9(3):200–210.
46.
LechartierB, HartkoornRC, ColeST. In vitro combination studies of benzothiazinone lead compound BTZ043 against Mycobacterium tuberculosis. Antimicrob Agents Chemother, 2012; 56(11):5790–5793.
47.
BahugunaA, RawatDS. An overview of new antitubercular drugs, drug candidates, and their targets. Med Res Rev, 2020; 40(1):263–292.
48.
TrefzerC, ŠkovierováH, BuroniS, et al.Benzothiazinones are suicide inhibitors of mycobacterial decaprenylphosphoryl-β-D-ribofuranose 2' oxidase DprE1. J Am Chem Soc, 2012; 134(2):912–915.
49.
MakarovV, ManinaG, MikusovaK, et al.Benzothiazinones kill Mycobacterium tuberculosis by blocking arabinan synthesis. Science, 2009; 324(5928):801–804.
50.
LupienA, VocatA, FooCS, et al.Optimized background regimen for treatment of active tuberculosis with the next-generation benzothiazinone macozinone (PBTZ169). Antimicrob Agents Chemother, 2018; 62(11):e00840-18.
51.
LechartierB, ColeST. Mode of action of clofazimine and combination therapy with benzothiazinones against Mycobacterium tuberculosis. Antimicrob Agents Chemother, 2015; 59(8):4457–4463.
52.
TahlanK, WilsonR, KastrinskyDB, et al.SQ109 targets MmpL3, a membrane transporter of trehalosemonomycolate involved in mycolic acid donation to the cell wall core of Mycobacterium tuberculosis. Antimicrob Agents Chemother, 2012; 56(4):1797–1809.
53.
ZhangB, LiJ, YangX, et al.Crystal structures of membrane transporter MmpL3, an anti-TB drug target. Cell, 2019; 176(3):636.e13–648.e13.
54.
ChenP, GearhartJ, ProtopopovaM, et al.Synergistic interactions of SQ109, a new ethylene diamine, with front-line antitubercular drugs in vitro. J Antimicrob Chemother, 2006; 58(2):332–337.
55.
ZhangD, WangY, LuJ, et al.In vitro activity of β-lactams in combination with β-lactamase inhibitors against multidrug-resistant Mycobacterium tuberculosis isolates. Antimicrob Agents Chemother, 2015; 60(1):393–399.
56.
Davies ForsmanL, GiskeCG, BruchfeldJ, et al.Meropenem-clavulanate has high in vitro activity against multidrug-resistant Mycobacterium tuberculosis. Int J Mycobacteriol, 2015; 4(Suppl 1):80–81.
57.
HugonnetJE, TremblayLW, BoshoffHI, et al.Meropenem-clavulanate is effective against extensively drug- resistant Mycobacterium tuberculosis. Science, 2009; 323(5918):1215–1218.
58.
LavollayM, ArthurM, FourgeaudM, et al.The peptidoglycan of stationary-phase Mycobacterium tuberculosis predominantly contains cross-links generated by L,D-transpeptidation. J Bacteriol, 2008; 190(12):4360–4366.
59.
DharN, DubéeV, BallellL, et al.Rapid cytolysis of Mycobacterium tuberculosis by faropenem, an orally bioavailable β-lactam antibiotic. Antimicrob Agents Chemother, 2015; 59(2):1308–1319.
60.
ReddyVM, EinckL, NacyCA. In vitro antimycobacterial activities of capuramycin analogues. Antimicrob Agents Chemother, 2008; 52(2):719–721.
61.
SiricillaS, MitachiK, WanB, et al.Discovery of a capuramycin analog that kills nonreplicating Mycobacterium tuberculosis and its synergistic effects with translocase I inhibitors. J Antibiot (Tokyo), 2015; 68(4):271–278.
62.
Piddock LJ. Teixobactin, the first of a new class of antibiotics discovered by iChip technology?. J Antimicrob Chemother, 2015; 70(10):2679–2680.
63.
LingLL, SchneiderT, PeoplesAJ, et al.A new antibiotic kills pathogens without detectable resistance. Nature, 2015; 517(7535):455–459.
64.
ShuklaR, Medeiros-SilvaJ, ParmarA, et al.Mode of action of teixobactins in cellular membranes. Nat Commun, 2020; 11(1):2848.
65.
FiersWD, CraigheadM, SinghI. Teixobactin and its analogues: A new hope in antibiotic discovery. ACS Infect Dis, 2017; 3(10):688–690.
66.
CaretteX, PlatigJ, YoungDC, et al.Multisystem analysis of Mycobacterium tuberculosis reveals kinase-dependent remodeling of the pathogen-environment interface. mBio, 2018; 9(2):e02333-17.
67.
HuszárS, SinghV, PolčicováA, et al.N-acetylglucosamine-1-phosphate transferase, WecA, as a validated drug target in Mycobacterium tuberculosis. Antimicrob Agents Chemother, 2017; 61(11):e01310-17.
68.
DegiacomiG, BelardinelliJM, PascaMR, et al.Promiscuous targets for antitubercular drug discovery: The paradigm of DprE1 and MmpL3. Appl Sci, 2020; 10(2):623.
69.
FaïonL, DjaoutK, FritaR, et al.Discovery of the first Mycobacterium tuberculosis MabA (FabG1) inhibitors through a fragment-based screening. Eur J Med Chem, 2020; 200:112440.
70.
AbrahamsKA, ChungCW, Ghidelli-DisseS, et al.Identification of KasA as the cellular target of an anti-tubercular scaffold. Nat Commun, 2016; 7:12581.
71.
StanleySA, KawateT, IwaseN, et al.Diarylcoumarins inhibit mycolic acid biosynthesis and kill Mycobacterium tuberculosis by targeting FadD32. Proc Natl Acad Sci U S A, 2013; 110(28):11565–11570.
72.
ShetyeGS, FranzblauSG, ChoS. New tuberculosis drug targets, their inhibitors, and potential therapeutic impact. Transl Res, 2020; 220:68–97.
MoreiraW, AzizDB, DickT. Boromycin kills mycobacterial persisters without detectable resistance. Front Microbiol, 2016; 7:199.
75.
KohnoJ, KawahataT, OtakeT, et al.Boromycin, an anti-HIV antibiotic. Biosci Biotechnol Biochem, 1996; 60(6):1036–1037.
76.
AbateG, RuminiskiPG, KumarM, et al.New verapamil analogs inhibit intracellular mycobacteria without affecting the functions of Mycobacterium-specific T cells. Antimicrob Agents Chemother, 2015; 60(3):1216–1225.
77.
HurdleJG, O'NeillAJ, ChopraI, et al.Targeting bacterial membrane function: An underexploited mechanism for treating persistent infections. Nat Rev Microbiol, 2011; 9(1):62–75.
78.
Brogden KA. Antimicrobial peptides: Pore formers or metabolic inhibitors in bacteria?. Nat Rev Microbiol, 2005; 3(3):238–250.
79.
da SilvaJL, GuptaS, OlivierKN, et al.Antimicrobial peptides against drug resistant Mycobacterium abscessus. Res Microbiol, 2020; 171(5–6):211–214.
80.
ParkY, HahmKS. Antimicrobial peptides (AMPs): Peptide structure and mode of action. J BiochemMol Biol, 2005; 38(5):507–516.
81.
MahlapuuM, HåkanssonJ, RingstadL, et al.Antimicrobial peptides: An emerging category of therapeutic agents. Front Cell Infect Microbiol, 2016; 6:194.
82.
AlonsoS, PetheK, RussellDG, et al.Lysosomal killing of Mycobacterium mediated by ubiquitin-derived peptides is enhanced by autophagy. Proc Natl Acad Sci U S A, 2007; 104(14):6031–6036.
83.
ElsamanT, MohamedMS, EltayibEM, et al.Xanthone: A promising antimycobacterial scaffold. Med Chem, 2021; 17(4):310–331.
84.
MukherjeeD, ZouH, LiuS, et al.Membrane-targeting AM-0016 kills mycobacterial persisters and shows low propensity for resistance development. Future Microbiol, 2016; 11:643–650.
85.
HuY, MathemaB, WangW, et al.Prevalence of multidrug-resistant pulmonary tuberculosis in counties with different duration of DOTS implementation in rural China. Microb Drug Resist, 2008; 14(3):227–232.
86.
CareyAF, RockJM, KriegerIV, et al.TnSeq of Mycobacterium tuberculosis clinical isolates reveals strain-specific antibiotic liabilities. PLoS Pathog, 2018; 14(3):e1006939.
87.
MiniasA, ŻukowskaL, LechowiczE, et al.Early drug development and evaluation of putative antitubercular compounds in the -omics era. Front Microbiol, 2021; 11:618168.
88.
MoopanarK, MvubuNE. Lineage-specific differences in lipid metabolism and its impact on clinical strains of Mycobacterium tuberculosis. Microb Pathog, 2020; 146:104250.
89.
ShakuM, EalandC, KanaBD. Cell surface biosynthesis and remodeling pathways in mycobacteria reveal new drug targets. Front Cell Infect Microbiol, 2020; 10:603382.
90.
CohenKA, El-HayT, WyresKL, et al.Paradoxical hypersusceptibility of drug-resistant Mycobacterium tuberculosis to β-lactam antibiotics. EBioMedicine, 2016; 9:170–179.
91.
AngKC, IbrahimP, GamLH. Analysis of differentially expressed proteins in late-stationary growth phase of Mycobacterium tuberculosis H37Rv. Biotechnol Appl Biochem, 2014; 61(2):153–164.
92.
FilippovaEV, KieserKJ, LuanCH, et al.Crystal structures of the transpeptidase domain of the Mycobacterium tuberculosis penicillin-binding protein PonA1 reveal potential mechanisms of antibiotic resistance. FEBS J, 2016; 283(12):2206–2218.
93.
AminAG, GoudeR, ShiLet al. EmbA is an essential arabinosyltransferase in Mycobacterium tuberculosis. Microbiology (Reading), 2008; 154(Pt 1):240–248.
94.
PaweŁczykJ, KremerL. The molecular genetics of mycolic acid biosynthesis. Microbiol Spectr, 2014; 2(4):MGM2-0003-2013.
95.
MottaI, CalcagnoA, BonoraS. Pharmacokinetics and pharmacogenetics of anti-tubercular drugs: A tool for treatment optimization?. Expert Opin Drug Metab Toxicol, 2018; 14(1):59–82.
96.
SaktiawatiAM, SturkenboomMG, StienstraY, et al.Impact of food on the pharmacokinetics of first-line anti-TB drugs in treatment-naive TB patients: A randomized cross-over trial. J Antimicrob Chemother, 2016; 71(3):703–710.
97.
SzumowskiJD, LynchJB. Profile of delamanid for the treatment of multidrug-resistant tuberculosis. Drug Des Devel Ther, 2015; 9:677–682.
98.
DavisA, MeintjesG, WilkinsonRJ. Treatment of tuberculous meningitis and its complications in adults. Curr Treat Options Neurol, 2018; 20(3):5.
99.
SturkenboomMGG, MärtsonAG, SvenssonEM, et al.Population pharmacokinetics and bayesian dose adjustment to advance TDM of anti-TB drugs. Clin Pharmacokinet, 2021; 60(6):685–710.
100.
DartoisVA, RubinEJ. Anti-tuberculosis treatment strategies and drug development: Challenges and priorities. Nat Rev Microbiol, 2022; 20(11):685–701.
101.
DubeyS, ValechaV. Prodrugs: A review. World J Pharm Res, 2014; 3(7):277–297.
102.
Augustynowicz-KopećE, ZwolskaZ. Bioavailability factors of isoniazid in fast and slow acetylators, healthy volunteers. Acta Pol Pharm, 2002; 59(6):452–457.
103.
PubChem [Internet]. Bethesda, MD: National Library of Medicine (US), National Center for Biotechnology Information; 2004-. PubChem Compound Summary for CID 6480466, Delamanid; [cited July 28, 2022].
104.
GarzaAZ, ParkSB, Kocz R. Drug Elimination. [Updated July 11, 2022]. In: StatPearls [Internet]. StatPearls Publishing; Treasure Island, FL; 2022.
105.
Currie GM. Pharmacology, part 1: Introduction to pharmacology and pharmacodynamics. J Nucl Med Technol, 2018; 46(2):81–86.
106.
CoxonGD, CraigD, CorralesRM, et al.Synthesis, antitubercular activity and mechanism of resistance of highly effective thiacetazone analogues. PLoS One, 2013; 8(1):e53162.
StancilSL, MirzayevF, Abdel-RahmanSM. Profiling pretomanid as a therapeutic option for TB infection: Evidence to date. Drug Des Devel Ther, 2021; 15:2815–2830.
109.
SinghR, DwivediSP, GaharwarUS, et al.Recent updates on drug resistance in Mycobacterium tuberculosis. J Appl Microbiol, 2020; 128(6):1547–1567.
110.
KaduraS, KingN, NakhoulM, et al.Systematic review of mutations associated with resistance to the new and repurposed Mycobacterium tuberculosis drugs bedaquiline, clofazimine, linezolid, delamanid and pretomanid. J Antimicrob Chemother, 2020; 75(8):2031–2043.
111.
KatsunoK, BurrowsJN, DuncanK, et al.Hit and lead criteria in drug discovery for infectious diseases of the developing world. Nat Rev Drug Discov, 2015; 14(11):751–758.
112.
Goldman RC. Why are membrane targets discovered by phenotypic screens and genome sequencing in Mycobacterium tuberculosis?. Tuberculosis (Edinb), 2013; 93(6):569–588.
