Department of Clinical Pharmacy, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
W. Harry Feinstone Center for Genomic Research, University of Memphis, Memphis, Tennessee, USA.
Antimicrob Agents Chemother. 2017 Aug 24;61(9). doi: 10.1128/AAC.00651-17. Print 2017 Sep.
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.
在新兴的非物种中， 特别令人关注，因为它是新生儿和重症监护病房患者医院获得性血流感染的原因。氟康唑和棘白菌素类药物被认为是治疗此类感染的有效方法，但最近有报道称 对氟康唑和棘白菌素类药物的耐药性表明这是一个日益严重的问题。本研究描述了一种新的抗真菌耐药机制，该机制影响唑类和棘白菌素类抗真菌药物在从患有人工瓣膜心内膜炎患者中获得的临床分离株中的敏感性。转录组分析表明，耐药分离株中几个基因的表达存在差异，包括固醇生物合成途径基因 、 、 、 、 、 和 的上调。全基因组测序显示，耐药分离株存在 突变，导致 G111R 氨基酸取代。甾醇谱表明，由于这种突变，甾醇去饱和酶活性降低。在耐药分离株中替换两个突变等位基因与敏感分离株的等位基因恢复了对所有唑类和棘白菌素类药物的野生型敏感性。在敏感和耐药分离株中破坏 导致甾醇去饱和酶活性丧失、高水平唑类耐药以及棘白菌素类药物中介至耐药表型。虽然 中的 突变导致唑类耐药，但棘白菌素 MIC 虽然升高，但仍在敏感范围内。这项工作表明， Erg3 中的 G111R 取代完全负责观察到的该 分离株中唑类和棘白菌素类药物敏感性的改变，并且是第一个报道 突变影响棘白菌素类药物敏感性的报告。
