CHARACTERIZATION OF A LIPOPEPTIDE-RESISTANT STRAIN OF CANDIDA-ALBICANS

Lipopeptides are antifungal agents that inhibit cell wall beta-(1,3)-g lucan biosynthesis in fungal organisms. A mutant resistant to lipopept ides was generated by UV mutagenesis and characterized. The Candida al bicans,ls mutant (LP3-1) was stable and showed resistance specificity to a broad range of lipopeptides and certain glycolipid inhibitors. Ot her antifungal agents with diverse modes of action had a normal minimu m inhibitory concentration profile for LP3-1 compared with the wild-ty pe strain (CCH 442). In the in vitro beta-(1,3)-glucan synthase assay, both the lipopeptides and papulacandin-related agents had considerabl y higher 50% inhibitory concentration values in the LP3-1 strain than in the wild-type strain. In reconstitution assays, the resistance fact or was associated with the integral membrane pellet rather than the pe ripheral GTP-binding protein. The LP3-1 strain had a membrane lipid pr ofile similar to that of the parent strain and was virulent in a murin e model of systemic candidiasis. Taken together, these results indicat e that the resistance factor is associated with the integral membrane component of beta-(1,3)-glucan synthase. Lipopeptides are common antif ungal agents encountered during screening of natural products. The LP3 -1 strain was resistant to natural product extracts known to contain v arious lipopeptides. Thus, LP3-1 can be used in a dereplication assay.