title: Nontoxic antimicrobials that evade drug resistance.
abstract: Drugs that act more promiscuously provide fewer routes for the emergence of resistant mutants. This benefit, however, often comes at the cost of serious off-target and dose-limiting toxicities. The classic example is the antifungal amphotericin B (AmB), which has evaded resistance for more than half a century. We report markedly less toxic amphotericins that nevertheless evade resistance. They are scalably accessed in just three steps from the natural product, and they bind their target (the fungal sterol ergosterol) with far greater selectivity than AmB. Hence, they are less toxic and far more effective in a mouse model of systemic candidiasis. To our surprise, exhaustive efforts to select for mutants resistant to these more selective compounds revealed that they are just as impervious to resistance as AmB. Thus, highly selective cytocidal action and the evasion of resistance are not mutually exclusive, suggesting practical routes to the discovery of less toxic, resistance-evasive therapies.
authors.affiliation: 1] Howard Hughes Medical Institute, Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA. [2] Roger Adam Laboratory, Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Davis
authors.affiliation: 1] Microbiology Graduate Program, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. [2] Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Vincent
authors.affiliation: 1] Howard Hughes Medical Institute, Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA. [2] Roger Adam Laboratory, Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Endo
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Luke
authors.initials: L
authors.lastname: Whitesell
authors.affiliation: 1] Department of Medicine, University of Wisconsin, Madison, Wisconsin, USA. [2] Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, Wisconsin, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Marchillo
authors.affiliation: 1] Department of Medicine, University of Wisconsin, Madison, Wisconsin, USA. [2] Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, Wisconsin, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Andes
authors.affiliation: 1] Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA. [2] Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Lindquist
authors.affiliation: 1] Howard Hughes Medical Institute, Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA. [2] Roger Adam Laboratory, Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
authors.forename: Martin D
authors.initials: MD
authors.lastname: Burke
mesh_terms: D000666:Amphotericin B / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001665:Binding Sites; D002175:Candida / Q000737:chemistry / Q000187:drug effects* / Q000254:growth & development / Q000472:pathogenicity; D002177:Candidiasis / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D025141:Drug Resistance, Fungal / Q000187:drug effects*; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects; D004875:Ergosterol / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D051379:Mice; D050296:Microbial Viability / Q000187:drug effects; D013329:Structure-Activity Relationship; D016019:Survival Analysis; D014508:Urea / Q000737:chemistry*
chemical_list: D000935:Antifungal Agents; D000666:Amphotericin B; D014508:Urea; D004875:Ergosterol