Lipid composition and polyene antibiotic resistance of <i>Candida albicans</i> mutants

Abstract

Four polyene-resistant mutants (C7, E4, C4, D10) of Candida albicans were derived by mutagenesis with N-methyl-N′-nitro-N-nitrosoguanidine followed by isolation on nystatin-containing medium. The mutants were cross resistant to amphotericin B, lucensomycin, and candicidin and showed the same order of increasing resistance to the four polyenes tested, i.e., C7 &lt; E4 &lt; C4 &lt; D10. Free sterols, sterol esters, and phospholipid fatty acids were analyzed in the mutants and sensitive parent strain. The lipids of C7 were the same as those of the sensitive parent strain. Mutant E4 contained lichesterol and other Δ 8 -sterols indicating a block at the Δ 8 → Δ 7 isomerase, and most of the sterol ester fraction consisted of 4,14-desmethyl sterols. The most resistant mutants C4 and D10 had reduced growth rates, alterations in phospholipid fatty acids, and the absence of 4,14-desmethyl sterols. Mutants C4 and D10 had similar lipid compositions with 24-methylenelanosterol as the major sterol and lesser amounts of obtusifoliol and lanosterol. The proportion of the total sterol that was esterified was low and similar (19–34%) in cultures of the mutants and of the sensitive strain harvested in the same stage of stationary growth. Total sterol content, however, increased with resistance. Polyene resistance was better correlated with the type of sterols in the total sterol pools rather than with the degree of esterification of the individual sterols, i.e., resistance increased with the presence of Δ 8 - and 4,14-methyl sterols. Our data indicate that factors other than or in addition to alterations in sterol and phospholipid patterns account for polyene resistance.