ERG2 and ERG24 are required for normal vacuolar physiology as well as Candida albicans pathogenicity in a murine model of disseminated but not vaginal candidiasis.

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ERG2 and ERG24 are required for normal vacuolar physiology as well as Candida albicans pathogenicity in a murine model of disseminated but not vaginal candidiasis.

Eukaryot Cell. 2015 Jul 31;

Authors: Luna-Tapia A, Peters BM, Eberle KE, Kerns ME, Foster TP, Marrero L, Noverr MC, Fidel PL, Palmer GE

Abstract
Several important classes of antifungal agents including the azoles, act by blocking ergosterol biosynthesis. It was recently reported that the azoles cause massive disruption of the fungal vacuole in the prevalent human pathogen Candida albicans. This is significant as normal vacuolar function is required to support C. albicans pathogenicity. This study examined the impact of the morpholine antifungals, which inhibit latter steps of ergosterol biosynthesis, upon C. albicans vacuolar integrity. It was found that overexpression of either the ERG2 or ERG24 genes, encoding C-8 sterol isomerase and C-14 sterol reductase respectively, suppresses C. albicans sensitivity to the morpholines. In addition, both erg2Δ/Δ and erg24Δ/Δ mutants are hypersensitive to the morpholines. These data are consistent with the antifungal activity of the morpholines depending upon the simultaneous inhibition of both Erg2p and Erg24p. The vacuoles within both erg2Δ/Δ and erg24Δ/Δ C. albicans strains exhibit an aberrant morphology and accumulate large quantities of the weak base quinacrine, indicating enhanced vacuolar acidification compared with the control strains. Both erg mutants exhibit significant defects in polarized hyphal growth and are avirulent in a mouse model of disseminated candidiasis. Surprisingly, in a mouse model of vaginal candidiasis, both mutants colonize at high levels and induce a pathogenic response similar to the controls. Thus while targeting Erg2p or Erg24p alone could provide a potentially efficacious therapy for disseminated candidiasis, it may not be an effective strategy to treat vaginal infections. The potential value of drugs targeting these enzymes as adjunctive therapies is discussed.

PMID: 26231054 [PubMed - as supplied by publisher]