Loss of C-5 Sterol Desaturase Activity Results in Increased Resistance to Azole and Echinocandin Antifungals in a Clinical Isolate of Candida parapsilosis

• Published in: Antimicrobial agents and chemotherapy Vol. 61; no. 9
• Main Authors: Rybak, Jeffrey M, Dickens, C Michael, Parker, Josie E, Caudle, Kelly E, Manigaba, Kayihura, Whaley, Sarah G, Nishimoto, Andrew T, Luna-Tapia, Arturo, Roy, Sujoy, Zhang, Qing, Barker, Katherine S, Palmer, Glen E, Sutter, Thomas R, Homayouni, Ramin, Wiederhold, Nathan P, Kelly, Steven L, Rogers, P David
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 01.09.2017
• Subjects: Antifungal Agents; Antifungal Agents - pharmacology; Azoles; Azoles - metabolism; Azoles - pharmacology; Candida parapsilosis; Candida parapsilosis - drug effects; Candida parapsilosis - genetics; Candida parapsilosis - isolation & purification; Cross Infection - drug therapy; Cross Infection - microbiology; Cross Infection - prevention & control; Drug Resistance, Multiple, Fungal - genetics; Echinocandins; Echinocandins - metabolism; Echinocandins - pharmacology; Ergosterol - biosynthesis; Ergosterol - genetics; Fungemia - drug therapy; Fungemia - microbiology; Fungemia - prevention & control; Gene Dosage - genetics; Genome, Fungal - genetics; Humans; Mechanisms of Resistance; Microbial Sensitivity Tests; Oxidoreductases; Oxidoreductases - genetics; Polymorphism, Single Nucleotide - genetics; molecular genetics; antimicrobial agents; Candida; antimicrobial activity; mycology; antifungal resistance; ergosterol
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.00651-17

Among emerging non- species, 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 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 , , , , , , and Whole-genome sequencing revealed that the resistant isolate possessed an 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 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 in 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 isolate and is the first report of an mutation influencing susceptibility to the echinocandins.