Characterization of a lipopeptide-resistant strain of Candida albicans.
Lipopeptides are antifungal agents that inhibit cell wall beta-(1,3)-glucan biosynthesis in fungal organisms. A mutant resistant to lipopeptides was generated by UV mutagenesis and characterized. The Candida albicans mutant (LP3-1) was stable and showed resistance specificity to a broad range of lipopeptides and certain glycolipid inhibitors. Other antifungal agents with diverse modes of action had a normal minimum inhibitory concentration profile for LP3-1 compared with the wild-type strain (CCH 442). In the in vitro beta-(1,3)-glucan synthase assay, both the lipopeptides and papulacandin-related agents had considerably higher 50% inhibitory concentration values in the LP3-1 strain than in the wild-type strain. In reconstitution assays, the resistance factor was associated with the integral membrane pellet rather than the peripheral GTP-binding protein. The LP3-1 strain had a membrane lipid profile similar to that of the parent strain and was virulent in a murine model of systemic candidiasis. Taken together, these results indicate that the resistance factor is associated with the integral membrane component of beta-(1,3)-glucan synthase. Lipopeptides are common antifungal agents encountered during screening of natural products. The LP3-1 strain was resistant to natural product extracts known to contain various lipopeptides. Thus, LP3-1 can be used in a dereplication assay.
Frost
D J
DJ
Department 47M, Abbott Laboratory, Abbott Park, IL 60064-3500, USA. david.j.frost@abbott.com
Knapp
M
M
Brandt
K
K
Shadron
A
A
Goldman
R C
RC
D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology; D001681:Biological Assay; D002176:Candida albicans / Q000187:drug effects* / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015966:Gene Expression Regulation, Fungal; D005964:Glucosyltransferases / Q000235:genetics* / Q000378:metabolism; D008055:Lipids / Q000032:analysis; D008074:Lipoproteins / Q000494:pharmacology*; D051379:Mice; D008826:Microbial Sensitivity Tests; D008861:Microsomes / Q000201:enzymology; D016296:Mutagenesis; D012680:Sensitivity and Specificity; D014466:Ultraviolet Rays
D000935:Antifungal Agents; D008055:Lipids; D008074:Lipoproteins; D005964:Glucosyltransferases; C040232:glucan synthase