Husain Farha, Yadav Anshuman, Sah Sudisht K, Hayes Jeffrey J, Rustchenko Elena
Department of Biochemistry and Biophysics, University of Rochester Medical Center, Rochester, NY 14642, USA.
Microorganisms. 2022 Dec 21;11(1):23. doi: 10.3390/microorganisms11010023.
is a prevalent fungal pathogen of humans. Understanding the development of decreased susceptibility to ECN drugs of this microbe is of substantial interest, as it is viewed as an intermediate step allowing the formation of resistance mutations. We used six previously characterized mutants that decreased caspofungin susceptibility either by acquiring aneuploidy of chromosome 5 (Ch5) or by aneuploidy-independent mechanisms. When we exposed these caspofungin-adapted mutants to caspofungin again, we obtained 60 evolved mutants with further decreases in caspofungin susceptibility, as determined with CLSI method. We show that the initial adaptation to caspofungin is coupled with the adaptation to other ECNs, such as micafungin and anidulafungin, in mutants with no ploidy change, but not in aneuploid mutants, which become more susceptible to micafungin and anidulafungin. Furthermore, we find that the initial mechanism of caspofungin adaptation determines the pattern of further adaptation as parentals with no ploidy change further adapt to all ECNs by relatively small decreases in susceptibility, whereas aneuploid parentals adapt to all ECNs, primarily by large decrease in susceptibilities. Our data suggest that either distinct or common mechanisms can govern adaptation to different ECNs.
是一种常见的人类真菌病原体。了解这种微生物对棘白菌素类药物敏感性降低的发展情况具有重大意义，因为这被视为形成耐药突变的中间步骤。我们使用了六个先前已表征的突变体，这些突变体通过获得5号染色体（Ch5）的非整倍体或通过非整倍体独立机制降低了对卡泊芬净的敏感性。当我们将这些适应卡泊芬净的突变体再次暴露于卡泊芬净时，我们获得了60个进化突变体，其对卡泊芬净的敏感性进一步降低，这是通过CLSI方法确定的。我们表明，在没有倍性变化的突变体中，对卡泊芬净的初始适应与对其他棘白菌素类药物（如米卡芬净和阿尼芬净）的适应相关，但在非整倍体突变体中则不然，非整倍体突变体对米卡芬净和阿尼芬净变得更敏感。此外，我们发现卡泊芬净适应的初始机制决定了进一步适应的模式，没有倍性变化的亲本通过敏感性相对较小的降低进一步适应所有棘白菌素类药物，而非整倍体亲本主要通过敏感性的大幅降低来适应所有棘白菌素类药物。我们的数据表明，不同的或共同的机制可以控制对不同棘白菌素类药物的适应。
