Genetic Analyses of Amphotericin B Susceptibility in Aspergillus fumigatus

Abstract

Aspergillus fumigatus is a ubiquitous saprophytic mold that can cause a range of clinical syndromes, from allergic reactions to invasive infections. Amphotericin B (AMB) is a polyene antifungal drug that has been used to treat a broad range of systemic mycoses since 1958, including as a primary treatment option against invasive aspergillosis in regions with high rates (≥10%) of environmental triazole resistance. However, cases of AMB-resistant A. fumigatus strains have been increasingly documented over the years, and high resistance rates were recently reported in Brazil and Canada. The objective of this study is to identify candidate mutations associated with AMB susceptibility using a genome-wide association analysis of natural strains, and to further investigate a subset of the mutations in their putative associations with differences in AMB minimum inhibitory concentration (MIC) and in growths at different AMB concentrations through the analysis of progeny from a laboratory genetic cross. Together, our results identified a total of 34 candidate single-nucleotide polymorphisms (SNPs) associated with AMB MIC differences—comprising 18 intergenic variants, 14 missense variants, one synonymous variant, and one non-coding transcript variant. Importantly, progeny from the genetic cross allowed us to identify putative SNP–SNP interactions impacting progeny growth at different AMB concentrations.

Population genomic analyses reveal high diversity, recombination and nosocomial transmission among Candida glabrata (Nakaseomyces glabrata) isolates causing invasive infections

“…Together, mutations in other genes and epigenetic mechanisms or interactions among multiple genes may play important roles in antifungal drug resistance in C. glabrata. Similar mechanisms for drug resistance have been demonstrated in several other fungi, including triazole resistance in C. albicans and amphotericin B resistance in A. fumigatus [104,105].…”

Genetic Structure and Triazole Antifungal Susceptibilities of Alternaria alternata from Greenhouses in Kunming, China

“…Together, these results suggested that different agricultural fungicides likely selected for different resistance mechanisms and that some of these mutations may make them more susceptible to other drugs. Allelic swaps and/or genetic crosses are needed in order to determine the quantitative contributions of each of these observed mutations to triazole susceptibilities ( 66 , 67 ).…”

“…Additional investigations using targeted mutagenesis, allele swaps, and/or genetic crosses are needed in order to determine their specific contributions to differences in triazole susceptibilities in A. alternata (e.g., 18, 19, 40, 42, 67, 68). Furthermore, whole-genome sequencing and genome-wide association studies of populations of strains with different MICs could help identify additional mutations outside the cyp51 gene that are associated with triazole susceptibilities in A. alternata ( 66 , 67 ).…”

Commercial Methods for Antifungal Susceptibility Testing of Saprophytic Molds: Can They Be Used to Detect Resistance?

“…There are no studies reporting genetic mutational changes leading to increasing amphotericin B MICs. Genetic analysis of amphotericin B resistant A. fumigatus isolates identified missense variants in genes tcsB, mpkC and catA and mutations in fumarylacetoacetate hydrolase associated with amphotericin B resistance [ 91 , 92 ]. There are observations of resistant Aspergillus spp.…”