Discovery of Ibomycin, a Complex Macrolactone that Exerts Antifungal Activity by Impeding Endocytic Trafficking and Membrane Function
Open accessAbstract
Natural products are invaluable historic sources of drugs for infectious diseases; however, the discovery of novel antimicrobial chemical scaffolds has waned in recent years. Concurrently, there is a pressing need for improved therapeutics to treat fungal infections. We employed a co-culture screen to identify ibomycin, a large polyketide macrolactone that has preferential killing activity against Cryptococcus neoformans. Using chemical and genome methods, we determined the structure of ibomycin and identified the biosynthetic cluster responsible for its synthesis. Chemogenomic profiling coupled with cell biological assays link ibomycin bioactivity to membrane function. The preferential activity of ibomycin toward C. neoformans is due to the ability of the compound to selectively permeate its cell wall. These results delineate a novel antifungal agent that is produced by one of the largest documented biosynthetic clusters to date and underscore the fact that there remains significant untapped chemical diversity of natural products with application in antimicrobial research.
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Screening a diverse collection of natural product-producing actinomycete strains led to identification of ibomycin as an inhibitor of C. neoformans growth, owing to its ability to permeate the fungal cell wall and affect membrane function by disrupting endosomal trafficking.
“Furthermore, screening a diverse collection of natural product-producing actinomycete strains led to identification of the glycosylated macrolactone ibomycin as an inhibitor of C. neoformans growth, owing to its ability to permeate the fungal cell wall and affect membrane function by disrupting endosomal trafficking90”
From Treatment strategies for cryptococcal infection: challenges, advances and future outlook (2021) · cites this paper as [90]
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- Authors
- Robbins, N., Spitzer, M., Wang, W., Waglechner, N., Patel, D. J., O’Brien, J. S., Ejim, L., Ejim, O., Tyers, M., & Wright, G. D.
- Affiliations
- Michael G. DeGroote Institute for Infectious Disease Research (CA)
- Enugu State University of Science and Technology (NG)
- Institute for Research in Immunology and Cancer (CA)
- Corresponding author
- Wright, Gerard D.
- Venue
- Cell Chemical Biology
- Publisher
- Elsevier BV
- Published
- 2016-11
- Volume
- 23
- Issue
- 11
- Pages
- 1383-1394
- ISSN
- 2451-9448 (ISSN-L)
- 2451-9456
- OpenAlex
- W2530023637
- Cited by
- 41
- References
- 47
- Citations by year
- 2026: 5 · 2025: 2 · 2024: 6 · 2023: 7 · 2022: 4 · 2021: 5 · 2020: 5 · 2019: 2 · 2018: 2 · 2017: 2 · 2016: 1
- FWCI
- 1.89
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 381 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell chemical biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research (FRN119572)
- Topics
- Health Sciences › Medicine › Pharmacology › Microbial Natural Products and Biosynthesis
- Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bioactive Natural Diterpenoids Research
- Keywords
- antifungal natural products, Cryptococcus neoformans, fungal infection, endosomal trafficking, membrane function, cell wall permeability, biosynthetic gene clusters, chemogenomic profiling, structure elucidation
- MeSH terms
- Antifungal Agents, Biological Products, Cell Wall, Cryptococcosis, Cryptococcus neoformans, Fungi, Humans, Lactones, Microbial Sensitivity Tests, Mycoses, Coculture Techniques, Drug Discovery
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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