Abstract
Invasive aspergillosis, mainly caused by Aspergillus fumigatus, can lead to severe clinical outcomes in immunocompromised individuals. Antifungal treatment, based on the use of azoles, is crucial to increase survival rates. However, the recent emergence of azole-resistant A. fumigatus isolates is affecting the efficacy of the clinical therapy and lowering the success rate of azole strategies against aspergillosis. Azole resistance mechanisms described to date are mainly associated with mutations in the azole target gene cyp51A that entail structural changes in Cyp51A or overexpression of the gene. However, strains lacking cyp51A modifications but resistant to clinical azoles have recently been detected. Some genes have been proposed as new players in azole resistance. In this study, the gene hmg1, recently related to azole resistance, and its paralogue hmg2 were studied in a collection of fifteen azole-resistant strains without cyp51A modifications. Both genes encode HMG-CoA reductases and are involved in the ergosterol biosynthesis. Several mutations located in the sterol sensing domain (SSD) of Hmg1 (D242Y, G307D/S, P309L, K319Q, Y368H, F390L and I412T) and Hmg2 (I235S, V303A, I312S, I360F and V397C) were detected. The role of these mutations in conferring azole resistance is discussed in this work.
Highlights
Aspergillus fumigatus is one of the most ubiquitous saprophytic fungi producing airborne conidia [1]
We focus on looking for single nucleotide polymorphisms (SNPs) in hmg1 and hmg2 that could explain the azole resistance phenotype of these isolates
Strains were considered resistant with Minimal inhibitory concentrations (MICs) over 1 mg/L to ITC and VCZ, 2 mg/L to ISV and 0.25 mg/L for POS according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints
Summary
Aspergillus fumigatus is one of the most ubiquitous saprophytic fungi producing airborne conidia [1]. Almost all resistance mechanisms found in ARAF strains were based on mutations in the azole target cyp51A [3,14,15,16]; ARAF strains without cyp51A modifications have started to be studied recently [17,18]. These isolates seem to be resistant to all clinical azole drugs without any cyp51A modification [19]. Several genes with different implications in the fungal cell have been proposed as A. fumigatus azole-resistance candidates. Other amino acid changes located outside the SSD, such as E105K, G466V, S541G, or H564Y have been described, but since they were found in azole-susceptible strains as well as in azole-resistant ones, they do not seem to be implicated in azole resistance [17,22,26,29]
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