Albehaijani Samah H I, Macreadie Ian, Morrissey C Orla, Boyce Kylie J
School of Science, RMIT University, Melbourne, VIC, Australia.
Department of Infectious Diseases, Alfred Health and Monash University, Melbourne, VIC, Australia.
JAC Antimicrob Resist. 2022 Apr 7;4(2):dlac033. doi: 10.1093/jacamr/dlac033. eCollection 2022 Apr.
Fungal infections are common life-threatening diseases amongst immunodeficient individuals. Invasive fungal disease is commonly treated with an azole antifungal agent, resulting in selection pressure and the emergence of drug resistance. Antifungal resistance is associated with higher mortality rates and treatment failure, making the current clinical management of fungal disease very challenging. Clinical isolates from a variety of fungi have been shown to contain mutations in the gene, encoding a component of the DNA mismatch repair pathway. Mutation of results in an elevated mutation rate that can increase the opportunity for selectively advantageous mutations to occur, accelerating the development of antifungal resistance.
To characterize the molecular mechanisms causing the microevolutionary emergence of antifungal resistance in mismatch repair mutants of .
The mechanisms resulting in the emergence of antifungal resistance were investigated using WGS, characterization of deletion mutants and measuring ploidy changes.
The genomes of resistant strains did not possess mutations in or other genes of the ergosterol biosynthesis pathway. Antifungal resistance was due to small contributions from mutations in many genes. does not directly affect ploidy changes.
This study provides evidence that resistance to fluconazole can evolve independently of mutations. A common microevolutionary route to the emergence of antifungal resistance involves the accumulation of mutations that alter stress signalling, cellular efflux, membrane trafficking, epigenetic modification and aneuploidy. This complex pattern of microevolution highlights the significant challenges posed both to diagnosis and treatment of drug-resistant fungal pathogens.
真菌感染在免疫缺陷个体中是常见的危及生命的疾病。侵袭性真菌病通常用唑类抗真菌药物治疗，这导致了选择压力和耐药性的出现。抗真菌耐药性与更高的死亡率和治疗失败相关，使得目前真菌病的临床管理极具挑战性。已显示来自多种真菌的临床分离株在编码DNA错配修复途径一个组分的基因中存在突变。该基因突变会导致突变率升高，从而增加选择性优势突变发生的机会，加速抗真菌耐药性的发展。
表征导致烟曲霉错配修复突变体中抗真菌耐药性微观进化出现的分子机制。
使用全基因组测序、缺失突变体表征和测量倍性变化来研究导致抗真菌耐药性出现的机制。
耐药菌株的基因组在麦角甾醇生物合成途径的该基因或其他基因中未发生突变。抗真菌耐药性是由于许多基因中的突变产生的微小影响所致。该基因不直接影响倍性变化。
本研究提供了证据表明对氟康唑的耐药性可独立于该基因突变而演变。抗真菌耐药性出现的常见微观进化途径涉及改变应激信号传导、细胞外排、膜运输、表观遗传修饰和非整倍体的突变积累。这种复杂的微观进化模式凸显了耐药真菌病原体诊断和治疗面临的重大挑战。
