Loss of C-5 sterol desaturase activity results in increased resistance to azole and echinocandin antifungals in a clinical isolate of candida parapsilosis

Jeffrey M. Rybak, C. Michael Dickens, Josie E. Parker, Kelly E. Caudle, Kayihura Manigaba, Sarah G. Whaley, Andrew T. Nishimoto, Arturo Luna-Tapia, Sujoy Roy, Qing Zhang, Katherine S. Barker, Glen E. Palmer, Thomas R. Sutter, Ramin Homayouni, Nathan P. Wiederhold, Steven L. Kelly, P. David Rogers

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Among emerging non-albicans Candida species, Candida parapsilosis is of particular concern as a cause of nosocomial bloodstream infections in neonatal and intensive care unit patients. While fluconazole and echinocandins are considered effective treatments for such infections, recent reports of fluconazole and echinocandin resistance in C. parapsilosis indicate a growing problem. The present study describes a novel mechanism of antifungal resistance in this organism affecting susceptibility to azole and echinocandin antifungals in a clinical isolate obtained from a patient with prosthetic valve endocarditis. Transcriptome analysis indicated differential expression of several genes in the resistant isolate, including upregulation of ergosterol biosynthesis pathway genes ERG2, ERG5, ERG6, ERG11, ERG24, ERG25, and UPC2. Whole-genome sequencing revealed that the resistant isolate possessed an ERG3 mutation resulting in a G111R amino acid substitution. Sterol profiles indicated a reduction in sterol desaturase activity as a result of this mutation. Replacement of both mutant alleles in the resistant isolate with the susceptible isolate’s allele restored wild-type susceptibility to all azoles and echinocandins tested. Disruption of ERG3 in the susceptible and resistant isolates resulted in a loss of sterol desaturase activity, high-level azole resistance, and an echinocandin-intermediate to -resistant phenotype. While disruption of ERG3 in C. albicans resulted in azole resistance, echinocandin MICs, while elevated, remained within the susceptible range. This work demonstrates that the G111R substitution in Erg3 is wholly responsible for the altered azole and echinocandin susceptibilities observed in this C. parapsilosis isolate and is the first report of an ERG3 mutation influencing susceptibility to the echinocandins.

Original languageEnglish (US)
Article numbere00651-17
JournalAntimicrobial agents and chemotherapy
Volume61
Issue number9
DOIs
StatePublished - Sep 2017

Keywords

  • Antifungal resistance
  • Antimicrobial activity
  • Antimicrobial agents
  • Candida
  • Ergosterol
  • Molecular genetics
  • Mycology

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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