title: Discovery of Ibomycin, a Complex Macrolactone that Exerts Antifungal Activity by Impeding Endocytic Trafficking and Membrane Function.
abstract: 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.
authors.affiliation: Department of Biochemistry and Biomedical Sciences, Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, ON L8N 3Z5, Canada.
authors.forename: Nicole
authors.initials: N
authors.lastname: Robbins
authors.affiliation: Department of Biochemistry and Biomedical Sciences, Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, ON L8N 3Z5, Canada.
authors.forename: Michaela
authors.initials: M
authors.lastname: Spitzer
authors.affiliation: Department of Biochemistry and Biomedical Sciences, Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, ON L8N 3Z5, Canada.
authors.forename: Wenliang
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Biomedical Sciences, Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, ON L8N 3Z5, Canada.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Waglechner
authors.affiliation: Department of Biochemistry and Biomedical Sciences, Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, ON L8N 3Z5, Canada.
authors.forename: Dhruv J
authors.initials: DJ
authors.lastname: Patel
authors.affiliation: Department of Biochemistry and Biomedical Sciences, Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, ON L8N 3Z5, Canada.
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: O'Brien
authors.affiliation: Department of Biochemistry and Biomedical Sciences, Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, ON L8N 3Z5, Canada.
authors.forename: Linda
authors.initials: L
authors.lastname: Ejim
authors.affiliation: College of Medicine, Enugu State University of Science and Technology, Enugu State, Nigeria.
authors.forename: Obi
authors.initials: O
authors.lastname: Ejim
authors.affiliation: Department of Medicine, Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC H3T 1J4, Canada.
authors.forename: Mike
authors.initials: M
authors.lastname: Tyers
authors.affiliation: Department of Biochemistry and Biomedical Sciences, Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, ON L8N 3Z5, Canada. Electronic address: wrightge@mcmaster.ca.
authors.forename: Gerard D
authors.initials: GD
authors.lastname: Wright
mesh_terms: D000935:Antifungal Agents / Q000737:chemistry* / Q000494:pharmacology*; D001688:Biological Products / Q000737:chemistry / Q000494:pharmacology; D002473:Cell Wall / Q000187:drug effects / Q000378:metabolism; D018920:Coculture Techniques; D003453:Cryptococcosis / Q000188:drug therapy* / Q000382:microbiology; D003455:Cryptococcus neoformans / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D055808:Drug Discovery; D005658:Fungi / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D006801:Humans; D007783:Lactones / Q000737:chemistry* / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D009181:Mycoses / Q000188:drug therapy / Q000382:microbiology
chemical_list: D000935:Antifungal Agents; D001688:Biological Products; D007783:Lactones
keywords: Actinomyces; Candida albicans; Cryptococcus neoformans; antifungal; cell membrane; chemogenomics; fungi; macrolactone; natural product; type I polyketide