A marine microbiome antifungal targets urgent-threat drug-resistant fungi

Marine bacteria produce a plethora of natural products that often have unusual chemical structures and corresponding reactivity, which sometimes translate into a valuable biological function. Zhang et al. used a metabolomic screen to zero in on microbial strains from the microbiome of a sea squirt t...

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Published inScience (American Association for the Advancement of Science) Vol. 370; no. 6519; pp. 974 - 978
Main Authors Zhang, Fan, Zhao, Miao, Braun, Doug R., Ericksen, Spencer S., Piotrowski, Jeff S., Nelson, Justin, Peng, Jian, Ananiev, Gene E., Chanana, Shaurya, Barns, Kenneth, Fossen, Jen, Sanchez, Hiram, Chevrette, Marc G., Guzei, Ilia A., Zhao, Changgui, Guo, Le, Tang, Weiping, Currie, Cameron R., Rajski, Scott R., Audhya, Anjon, Andes, David R., Bugni, Tim S.
Format Journal Article
LanguageEnglish
Published United States The American Association for the Advancement of Science 20.11.2020
Subjects
Animals
Antifungal activity
Antifungal agents
Antifungal Agents - chemistry
Antifungal Agents - pharmacology
Antifungal Agents - therapeutic use
Benzopyrans - chemistry
Benzopyrans - pharmacology
Benzopyrans - therapeutic use
Biocompatibility
Candida - drug effects
Candida auris
Candidiasis, Invasive - drug therapy
Cutting resistance
Disease Models, Animal
Drug resistance
Drug Resistance, Multiple, Fungal
Drugs
Exploration
Fungal infections
Fungal Proteins - metabolism
Fungi
Fungicides
Infectious diseases
Isoquinolines - chemistry
Isoquinolines - pharmacology
Isoquinolines - therapeutic use
Marine animals
Marine organisms
Metabolomics
Mice
Microbiomes
Microbiota
Micromonospora - chemistry
Microorganisms
Mode of action
Multidrug resistance
Narcotics
Natural products
Pathogens
Phospholipid Transfer Proteins - metabolism
Safety
Toxicity
Urochordata - microbiology
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Summary:Marine bacteria produce a plethora of natural products that often have unusual chemical structures and corresponding reactivity, which sometimes translate into a valuable biological function. Zhang et al. used a metabolomic screen to zero in on microbial strains from the microbiome of a sea squirt that produces a high diversity of chemical structures. They then screened these molecules for inhibition of fungi (see the Perspective by Cowen). A polycyclic molecule dubbed turbinmicin possessed potent antifungal activity against the multidrug-resistant fungal pathogens Candida auris and Aspergillus fumigatus . Preliminary mechanism-of-action and mouse toxicity studies suggest that this molecule works though a fungus-specific pathway and is well tolerated at therapeutic doses. Science , this issue p. 974 ; see also p. 906 A natural product from a marine bacterium shows selective activity against fungal pathogens. New antifungal drugs are urgently needed to address the emergence and transcontinental spread of fungal infectious diseases, such as pandrug-resistant Candida auris. Leveraging the microbiomes of marine animals and cutting-edge metabolomics and genomic tools, we identified encouraging lead antifungal molecules with in vivo efficacy. The most promising lead, turbinmicin, displays potent in vitro and mouse-model efficacy toward multiple-drug–resistant fungal pathogens, exhibits a wide safety index, and functions through a fungal-specific mode of action, targeting Sec14 of the vesicular trafficking pathway. The efficacy, safety, and mode of action distinct from other antifungal drugs make turbinmicin a highly promising antifungal drug lead to help address devastating global fungal pathogens such as C. auris.
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These authors contributed equally to this work.
Author contributions: Consistent with CRediT taxonomy, the roles of contributing authors are as follows: Conceptualization: T.S.B., D.R.A., C.R.C., and W.T.; methodology: F.Z., M.Z., D.R.B., J.S.P., J.N., J.P., G.E.A., S.C., K.B.,I.A.G., C.Z., and L.G.; software: S.C., J.P., T.S.B., S.S.E., and J.S.P.; validation: I.A.G., F.Z., M.Z., D.R.B., A.A., D.R.A., and M.G.C.; formal analysis: F.Z., M.Z., S.S.E., J.S.P., J.N., G.E.A., J.F., A.A., and M.G.C.; investigation: F.Z., M.Z., S.S.E., C.Z., H.S., L.G., and A.A.; resources: D.R.B., S.S.E., G.E.A., S.C., K.B., H.S., and I.A.G.; data curation: F.Z., M.Z., G.E.A., W.T., C.R.C., S.R.R., A.A., D.R.A., and T.S.B.; writing—original draft: F.Z., S.R.R., M.Z., T.S.B., and D.R.A.; writing—review and editing: F.Z., J.F., H.S., J.S.P., C.R.C., S.R.R., A.A., D.R.A., and T.S.B.; visualization: T.S.B., D.R.A., C.R.C., and A.A.; supervision: T.S.B., D.R.A., C.R.C., and W.T.; project administration: D.R.A., T.S.B., and W.T.; and funding acquisition: D.R.A., C.R.C., T.S.B., and A.A.
ISSN:0036-8075
1095-9203
1095-9203
DOI:10.1126/science.abd6919