Improving detection and diagnosis of antimicrobial resistance in Aspergillus fumigatus
( IMPROVE-ASP )

Azole resistance is an emerging concern in Aspergillus fumigatus, a fungus that may cause life-threatening infections in humans and animals. A. fumigatus is listed as one of 4 fungal pathogens in the 2022 WHO critical priority pathogen group, which is the first global effort to systematically prioritize fungal pathogens, considering their unmet research needs and perceived public health importance. Resistance in A. fumigatus is mainly caused by mutations in the Cyp51A-gene, which commonly causes a pan-azole-resistant phenotype. Alternative treatment options to azoles are very limited although new compounds are under development, most notably olorofim (OLO). Detection of azole resistance is challenging as current tests have limited sensitivity. In addition, the variation in Cyp51A resistance genotypes that impact on azole MIC is increasing and a large subset of 20% of isolates with high azoles MICs have unknown resistance mechanisms. Our proposal aims to IMPROVE current diagnostic tools by developing reverse complement (RC)-PCR, characterising critical single nucleotide polymorphisms (SNPs) and identifying new resistance mechanisms in azole-resistant A. fumigatus. In addition, we will IMPROVE current agar-based screening tools to allow rapid screening for azole resistance and adding OLO resistance screening. Our studies will provide improved reference diagnostics as well as low cost screening tools benefiting patients with Aspergillus diseases. These tools and insights will also benefit international One Health resistance surveillance programs.