Biology subjects

Hemmings, S.

Publications and source records attributed to Hemmings, S..

2 recordsLinked to original sources

bioRxiv2022

Landscape-scale exposure to multiazole-resistant Aspergillus fumigatus bioaerosols

We demonstrate country-wide exposures to aerosolized spores of a human fungal pathogen, Aspergillus fumigatus, that has acquired resistance to first line azole clinical antifungal drugs. Assisted by a network of citizen scientists across the United Kingdom, we show that 1 in 20 viable aerosolized spores of this mold are resistant to the agricultural fungicide tebuconazole and 1 in 140 spores are resistant to the four most used azoles for treating clinical aspergillosis infections. Season and proximity to industrial composters were associated with growth of A. fumigatus from air samples, but not with the presence of azole resistance, and hotspots were not stable between sampling periods suggesting a high degree of atmospheric mixing. Genomic analysis shows no distinction between those resistant genotypes found in the environment and in patients, indicating that ~40% (58/150 sequenced genomes) of azole-resistant A. fumigatus infections are acquired from environmental exposures. Due to the ubiquity of this measured exposure, it is crucial that we determine source(s) of azole-resistant A. fumigatus, who is at greatest risk of exposure and how to mitigate these exposures, in order to minimize treatment failure in patients with aspergillosis. One sentence summaryUK-wide citizen science surveillance finds a ubiquitous exposure to aerosolized spores of a human fungal pathogen that have evolved in the environment cross-resistance to essential clinical antifungal drugs

microbiology↗

bioRxiv2021

Olorofim and the azoles are antagonistic in Aspergillus fumigatus and functional genomic screens reveal mechanisms of cross resistance.

Aspergillosis, in its various manifestations, is a major cause of morbidity and mortality. Very few classes of antifungal drugs have been approved for clinical use to treat these diseases and resistance to the first line therapeutic class, the triazoles, is increasing. A new class of antifungals that target pyrimidine biosynthesis, the orotomides, are currently in development with the first compound in this class, olorofim in late-stage clinical trials. In this study, we identify an antagonistic action of the triazoles on the action of olorofim. We show that this antagonism is the result of an azole induced upregulation of the pyrimidine biosynthesis pathway and regulation. Intriguingly, we show that loss of function in the higher order transcription factor, HapB a member of the heterotrimeric HapB/C/E (CBC) complex or the regulator of nitrogen metabolic genes AreA, leads to cross resistance to both the azoles and olorofim indicating that factors that govern resistance are under common regulatory control. However loss of azole induced antagonism requires decoupling of the pyrimidine biosynthetic pathway in a manner independent of the action of a single transcription factor. Our study provides a first insight into antagonism between the azoles and olorofim through dysregulation of the pyrimidine and ergosterol pathway, showing complex crosstalk between these two pathways.

microbiology↗