Pyrrolocin A,a 3-Decalinoyltetramic Acid with Selective Biological Activity,Isolated from Amazonian Cultures of the Novel Endophyte Diaporthales sp. E6927E
Free accessResearch articleFirst published online October, 2015
Pyrrolocin A,a 3-Decalinoyltetramic Acid with Selective Biological Activity,Isolated from Amazonian Cultures of the Novel Endophyte Diaporthales sp. E6927E
Natural products remain an important source of new therapeutics for emerging drug-resistant pathogens like Candida albicans, which particularly affects immunocompromised patients. A bioactive 3-decalinoyltetramic acid, pyrrolocin A, was isolated from extracts of a novel Amazonian fungal endophyte, E6927E, of the Diaporthales family. The structure of the natural product was solved using NMR and CD spectroscopy and it is structurally related to the fungal setins, equisetin and phomasetin, which are well-characterized tetramic acid antibiotics specific for Gram-positive organisms. We show that the compound inhibits growth of Staphylococcus aureus and Enterococcus faecalis. It shows selective and potent bioactivity against fungal strains, with an MIC of 4 μg/mL for C. albicans, 100 μg/mL for Aspergillus sp. and greater than 100 μg/mL for Saccharomyces cerevisiae. Further, the compound is less toxic to mammalian cells (IC50 = 150 μg/mL), with an inhibitory concentration greater than forty times that for C. albicans. Pyrrolocin A retained potent activity against eight out of seventeen strains of clinical Candida sp. isolates tested.
BrownDG, ListerT, May-DrackaTL. (2014) New natural products as new leads for antibacterial drug discovery. Bioorganic & Medicinal Chemistry Letters, 24, 413–418.
2.
LamKS. (2007) New aspects of natural products in drug discovery. Trends in Microbiology, 15, 279–289
3.
SalemmeFR, SpurlinoJ, BoneR. (1997) Serendipity meets precision: the integration of structure-based drug design and combinatorial chemistry for efficient drug discovery. Structure, 5, 319–324
4.
ShuYZ. (1998) Recent natural products based drug development: a pharmaceutical industry perspective. Journal of Natural Products, 61, 1053–1071.
5.
CordellGA, ShinYG. (1999) Finding the needle in the haystack. The dereplication of natural product extracts. Pure and Applied Chemistry, 71, 1089–1094.
6.
WatveMG, TickooR, JogMM, BholeBD. (2001) How many antibiotics are produced by the genus Streptomyces?Archives of Microbiology, 176, 386–390.
7.
SoginML, MorrisonHG, HuberJA, Mark WelchD, HuseSM, NealPR, ArrietaJM, HerndlGJ. (2006) Microbial diversity in the deep sea and the underexplored “rare biosphere”. Proceedings of the National Academy of Sciences of the United States of America, 103, 12115–12120
8.
WardDM, WellerR, BatesonMM. (1990) 16S rRNA sequences reveal numerous uncultured microorganisms in a natural community. Nature, 345, 63–65
9.
HandelsmanJ, RondonMR, BradySF, ClardyJ, GoodmanRM. (1998) Molecular biological access to the chemistry of unknown soil microbes: a new frontier for natural products. Chemistry & Biology, 5, R245–249.
JadulcoRC, KochM, KakuleTB, SchmidtEW, OrendtA, HeH, JansoJE, CarterGT, LarsonEC, PondC, MatainahoTK, BarrowsLR. (2014) Isolation of pyrrolocins A-C: cis- and trans-decalin tetramic acid antibiotics from an endophytic fungal-derived pathway. Journal of Natural Products, 77, 2537–2544.
12.
BurmeisterHR. (1976) Antibiotic equisetin and method of production. U.S. Patent: 3,959,468 A.
13.
SinghSB, ZinkDL, GoetzMA, DombrowskiAW, PolishookJD, HazudaDJ. (1998) Equisetin and a novel opposite stereochemical homolog phomasetin, two fungal metabolites as inhibitors of HIV-1 integrase. Tetrahedron Letters, 39, 2243–2246.
14.
WinterG. (1886) Die Pilze Deutschlands, Osterreichs und der Schweiz. II. Abteilung: Ascomyceten: Gymnoasceen. Rabenhorst's Kryptogamen-Flora, 1(2), Verlag E. Kummer, Leipzig.
15.
CastleburyLA, RossmanAY, JaklitschWJ, VasilyevaLN. (2002) A preliminary overview of the Diaporthales based on large subunit nuclear ribosomal DNA sequences. Mycologia, 94, 1017–1031
16.
SogonovMV, CastleburyL, RossmanA, MejiaL, WhiteJ. (2008) Leaf-inhabiting genera of the Gnomoniaceae, Diaporthales. Studies in Mycology, 62, 1–77.
17.
KlebahnH. (1918) Haupt-und Nebenfruchtformen der Askomyzeten: Eine darstellung eigener und der in der literatur niedergelegten beobachtungen ilber die zusammenhange zwischen schlauchfrilchten undkonidienfruchtformen. Gebrüder Borntraeger, pp 395
18.
RehmH. (1885) Ascomyceten: Sclerotinia baccarum. Fasc. XVI. Hedwigia, 24, 7–17.
19.
MonodM. (1983) Monographie taxonomique des Gnomoniaceae. Beihefte zur Sydowia. Annates Mycologici, Ser, 2, 1–315
20.
RossmanAY, FarrDF, CastleburyLA. (2007) A review of the phylogeny and biology of the Diaporthales. Mycoscience, 48, 135–144.
21.
BarengoN, SieberTN, HoldenriederO. (2000) Diversity of endophytic mycobiota in leaves and twigs of pubescent birch (Betula pubescens). Sydowia, 52, 305–320
22.
KanekoS, KobayashiT. (1984) Fungi inhabiting fagaceous trees V. Three species of Diaporthaceae on evergreen oak leaves. Transactions of the Mycological Society of Japan, 25, 11–19.
23.
HazudaD, BlauCU, FelockP, HastingsJ, PramanikB, WolfeA, BushmanF, FarnetC, GoetzM, WilliamsM, SilvermanK, LinghamR, SinghS. (1999) Isolation and characterization of novel human immunodeficiency virus integrase inhibitors from fungal metabolites. Antiviral Chemistry & Chemotherapy, 10, 63–70
24.
MarforiEC, KajiyamaS, FukusakiE, KobayashiA. (2002) Trichosetin, a novel tetramic acid antibiotic produced in dual culture of Trichoderma harzianum and Catharanthus roseus callus. Zeitschrift fur Naturforschung C, Journal of Biosciences, 57, 465–470
25.
MarforiEC, BambaT, KajiyamaSi, FukusakiE-i, KobayashiA. (2002) Biosynthetic studies of the tetramic acid antibiotic trichosetin. Tetrahedron, 58, 6655–6658
26.
HerathK, JayasuriyaH, ZinkDL, SigmundJ, VicenteF, de la CruzM, BasilioA, BillsGF, PolishookJD, DonaldR, PhillipsJ, GoetzM, SinghSB. (2012) Isolation, structure elucidation, and antibacterial activity of methiosetin, a tetramic acid from a tropical sooty mold (Capnodium sp.). Journal of Natural Products, 75, 420–424
27.
WheelerM, StipanovicR, PuckhaberL. (1999) Phytotoxicity of equisetin and epi-equisetin isolated from Fusarium equiseti and F. pallidoroseum. Mycological Research, 103, 967–973
28.
HaleckerS, SurupF, KuhnertE, MohrKI, BrockNL, DickschatJS, JunkerC, SchulzB, StadlerM. (2014) Hymenosetin, a 3-decalinoyltetramic acid antibiotic from cultures of the ash dieback pathogen, Hymenoscyphus pseudoalbidus. Phytochemistry, 100, 86–91
29.
WhittJ, ShipleySM, NewmanDJ, ZuckKM. (2014) Tetramic acid analogues produced by coculture of Saccharopolyspora erythraea with Fusarium pallidoroseum. Journal of Natural Products, 77, 173–177
30.
InokoshiJ, ShigetaN, FukudaT, UchidaR, NonakaK, MasumaR, TomodaH. (2013) Epi-trichosetin, a new undecaprenyl pyrophosphate synthase inhibitor, produced by Fusarium oxysporum FKI-4553. The Journal of Antibiotics (Tokyo), 66, 549–554
31.
VertesyL, KnaufM, Markus-ErbA, TotiL, Raynal-WetzelM-C, FassyF. (2003) Coniosetin and derivatives thereof, process for the preparation and the use thereof. U.S. Patent: 6,599,930 B2.
32.
Bascom-SlackCA, ArnoldAE, StrobelSA. (2012) IBI series winner. Student-directed discovery of the plant microbiome and its products. Science, 338, 485–486
33.
StrobelG, DaisyB. (2003) Bioprospecting for microbial endophytes and their natural products. Microbiology and Molecular Biology Reviews, 67, 491–502.
34.
GriffinMA, SpakowiczDJ, GianoulisTA, StrobelSA. (2010) Volatile organic compound production by organisms in the genus Ascocoryne and a re-evaluation of myco-diesel production by NRRL 50072. Microbiology, 156, 3814–3829.
35.
EdgarRC. (2004) MUSCLE: multiple sequence alignment with high accuracy and high throughput. Nucleic Acids Research, 32, 1792–1797
36.
SmithSA, DunnCW. (2008) Phyutility: a phyloinformatics tool for trees, alignments and molecular data. Bioinformatics, 24, 715–716.
37.
DarribaD, TaboadaGL, DoalloR, PosadaD. (2012) jModelTest 2: more models, new heuristics and parallel computing. Nature Methods, 9, 772–772
38.
GuindonS, GascuelO. (2003) A simple, fast, and accurate algorithm to estimate large phylogenies by maximum likelihood. Systematic Biology, 52, 696–704.
39.
MaddisonWP, MaddisonD. (2014) Mesquite: a modular system for evolutionary analysis, v.3.01
StamatakisA. (2014) RAxML version 8: atool for phylogenetic analysis and post-analysis of large phylogenies. Bioinformatics, 30, 1312–1313.
42.
WhiteTJ, BrunsT, LeeS, TaylorJ. (1990) Amplification and direct sequencing of fungal ribosomal RNA genes for phylogenetics. PCR protocols: a guide to methods and applications, 18, 315–322.
43.
SpataforaJW, MitchellTG, VilgalysR. (1995) Analysis of genes coding for small-subunit rRNA sequences in studying phylogenetics of dematiaceous fungal pathogens. Journal of Clinical Microbiology, 33, 1322–1326.
44.
VilgalysR, SunBL. (1994) Ancient and recent patterns of geographic speciation in the oyster mushroom Pleurotus revealed by phylogenetic analysis of ribosomal DNA sequences. Proceedings of the National Academy of Sciences, 91, 4599–4603.
45.
VilgalysR, HesterM. (1990) Rapid genetic identification and mapping of enzymatically amplified ribosomal DNA from several Cryptococcus species. Journal of Bacteriology, 172, 4238–4246.
46.
RehnerSA, BuckleyE. (2005) A Beauveria phylogeny inferred from nuclear ITS and EFl-α sequences: evidence for cryptic diversification and links to Cordyceps teleomorphs. Mycologia, 97, 84–98.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
