The environmental use of azole fungicides has led to selective sweeps across multiple loci in the Aspergillus fumigatus genome causing the rapid global expansion of a genetically distinct cluster of resistant genotypes. Isolates within this cluster are also more likely to be resistant to agricultural antifungals with unrelated modes of action. Here we show that this cluster is not only multi-azole resistant but has increased propensity to develop resistance to next generation antifungals because of variants in the DNA mismatch repair system. A variant in msh6-G233A is found almost exclusively within azole resistant isolates harbouring the canonical cyp51A azole resistance allelic variant TR₃₄/L98H. Naturally occurring isolates with this msh6 variant display up to 5-times higher rate of mutation, leading to an increased likelihood of evolving resistance to other antifungals. Furthermore, unlike hypermutator strains, the G233A variant conveys no measurable fitness cost and has become globally distributed. Our findings further suggest that resistance to next-generation antifungals is more likely to emerge within organisms that are already multi-azole resistant due to close linkage between TR₃₄/L98H and msh6-G233A, posing a major problem due to the prospect of dual use of novel antifungals in clinical and agricultural settings.

唑类杀菌剂的环境使用导致对烟曲霉基因组中多个位点的选择性扫描，导致遗传上不同的抗性基因型簇的快速全球扩展。该簇中的分离株也更有可能对具有不相关作用方式的农业抗真菌药产生耐药性。在这里，我们表明该簇不仅具有多唑类耐药性，而且由于 DNA 错配修复系统的变异，该簇对下一代抗真菌药产生耐药性的倾向增加。msh6-G233A 的变体几乎完全存在于含有经典 cyp51A 唑类抗性等位基因变体 TR₃₄/L98H 的唑类抗性分离株中。具有这种 msh6 变体的天然分离株的突变率高出 5 倍，导致对其他抗真菌药产生耐药性的可能性增加。此外，与 hypermutator 菌株不同，G233A 变体没有可测量的适应度成本，并且已在全球范围内分布。我们的研究结果进一步表明，由于 TR₃₄/L98H 和 msh6-G233A 之间的密切联系，对下一代抗真菌药的耐药性更有可能出现在已经对多唑类药物耐药的生物体中，由于新型抗真菌药在临床和农业环境中双重使用的前景而构成重大问题。