| Summary: | One of the systems responsible for the recognition and repair of mistakes occurring during cell replication is the DNA mismatch repair (MMR) system. Two major protein complexes constitute the MMR pathway: MutS and MutL. Here, we investigated the possible relation of four <i>A. fumigatus</i> MMR genes (<i>msh</i>2, <i>msh</i>6, <i>pms</i>1, and <i>mlh</i>1) with the development of azole resistance related to the phenomenon of multi-drug resistance. We examined the MMR gene variations in 163 <i>Aspergillus fumigatus</i> genomes. Our analysis showed that genes <i>msh</i>2, <i>pms</i>1, and <i>mlh</i>1 have low genetic variability and do not seem to correlate with drug resistance. In contrast, there is a nonsynonymous mutation (G240A) in the <i>msh</i>6 gene that is harbored by 42% of the strains, most of them also harboring the TR<sub>34</sub>/L98H azole resistance mechanism in <i>cyp</i>51A. The <i>msh</i>6 gene was deleted in the <i>aku</i>B<sup>KU80</sup> <i>A. fumigatus</i> strain, and the ∆<i>msh</i>6 isolates were analyzed for fitness, azole susceptibility, and virulence capacity, showing no differences compared with the <i>aku</i>B<sup>KU80</sup> parental strain. Wild-type <i>msh</i>6 and Δ<i>msh</i>6 strains were grown on high concentrations of azole and other non-azole fungicides used in crop protection. A 10- and 2-fold higher mutation frequency in genes that confer resistance to boscalid and benomyl, respectively, were observed in Δ<i>msh</i>6 strains compared to the wild-type. This study suggests a link between Msh6 and fungicide resistance acquisition.
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