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Molecular Mechanisms of Drug Resistance in Clinical Candida Species Isolated from Tunisian Hospitals / J Eddouzi; J. E Parker; L. A Vale-Silva; A Coste; F Ischer; S Kelly; M Manai; D Sanglard; Steven Kelly; Josie Parker
Antimicrobial Agents and Chemotherapy, Volume: 57, Issue: 7, Pages: 3182 - 3193
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Antifungal resistance of Candida species is a clinical problem in the management of diseases caused by these pathogens. In this study we identified from a collection of 423 clinical samples taken from Tunisian hospitals two clinical Candida species (C. albicans JEY355 and C. tropicalis JEY162) with...
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Antifungal resistance of Candida species is a clinical problem in the management of diseases caused by these pathogens. In this study we identified from a collection of 423 clinical samples taken from Tunisian hospitals two clinical Candida species (C. albicans JEY355 and C. tropicalis JEY162) with decreased susceptibility to azoles and polyenes. JEY355 exhibited fluconazole MIC of 8 μg/ml. Azole-resistance in C. albicans JEY355 was mainly caused by overexpression of a multidrug efflux pump of the major facilitator superfamily, Mdr1. The regulator of Mdr1, MRR1, contained a yet unknown gain-of-function mutation (V877F) causing MDR1 overexpression. The C. tropicalis JEY162 isolate showed cross-resistance between FLC (MIC >128 μg/ml), voriconazole (MIC >16 μg/ml) and amphotericin B (MIC >32 μg/ml). Sterol analysis using gas chromatography-mass spectrometry revealed that ergosterol was undetectable in JEY162 and that it accumulated 14α-methyl fecosterol, thus indicating a perturbation in the function of at least two main ergosterol biosynthesis proteins (Erg11 and Erg3). Sequence analyses of CtERG11 and CtERG3 from JEY162 revealed a deletion of 132 nucleotides and a single amino acid substitution (S258F), respectively. These two alleles were demonstrated as non-functional and thus are consistent with previous studies showing that ERG11 mutants can only survive in combination with other ERG3 mutations. CtERG3 and CtERG11 wild-type alleles were replaced by the defective genes in a wild-type C. tropicalis strain resulting in drug resistance phenotype identical to JEY162. This genetic evidence demonstrated that CtERG3 and CtERG11 mutations participated in drug resistance. During reconstitution of the drug resistance in C. tropicalis, a strain was obtained harboring only defective Cterg11 allele and containing as major sterol the toxic metabolite 14α-methyl-ergosta-8,24 (28)-dien-3α, 6β-diol, thus suggesting that ERG3 was still functional. This strain therefore challenged the current belief that ERG11 mutations cannot be viable unless accompanied by compensatory mutations. In conclusion, this study, besides identifying a novel MRR1 mutation in C. albicans, constitutes the first report on a clinical C. tropicalis with defective activity of sterol 14α-demethylase and sterol Δ5,6-desaturase leading to azole-polyene cross-resistance.
Swansea University Medical School