The Influence of Genetic Stability on Virulence and Azole Resistance.

Genetic stability is extremely important for the survival of every living organism, and a very complex set of genes has evolved to cope with DNA repair upon DNA damage. Here, we investigated the AtmA (Ataxia-telangiectasia mutated, ATM) and AtrA kinases, and how they impact virulence and the evolution of azole resistance. We demonstrated that and null mutants are haploid and have a discrete chromosomal polymorphism. The Δ and Δ strains are sensitive to several DNA-damaging agents, but surprisingly both strains were more resistant than the wild-type strain to paraquat, menadione, and hydrogen peroxide. The and genes showed synthetic lethality emphasizing the cooperation between both enzymes and their consequent redundancy. The lack of and does not cause any significant virulence reduction in in a neutropenic murine model of invasive pulmonary aspergillosis and in the invertebrate alternative model Wild-type, Δ, and Δ populations that were previously transferred 10 times in minimal medium (MM) in the absence of voriconazole have not shown any significant changes in drug resistance acquisition. In contrast, Δ and Δ populations that similarly evolved in the presence of a subinhibitory concentration of voriconazole showed an ∼5-10-fold increase when compared to the original minimal inhibitory concentration (MIC) values. There are discrete alterations in the voriconazole target Cyp51A/Erg11A or / and/or Cdr1B efflux transporter overexpression that do not seem to be the main mechanisms to explain voriconazole resistance in these evolved populations. Taken together, these results suggest that genetic instability caused by Δ and Δ mutations can confer an adaptive advantage, mainly in the intensity of voriconazole resistance acquisition.