[Final accepted version, unedited] Understanding the Environmental Drivers of Clinical Azole Resistance in Aspergillus Spp.

Aspergilli are ubiquitous fungal pathogens associated with several life-threatening infections, especially in immunocompromised patients. Azoles are the first line of treatment for most Aspergillus related infections. However, resistance to these chemicals has emerged, often conferred by the presence of mutations in a key component of the ergosterol biosynthetic pathway, lanosterol 14 alpha-demethylase (Cyp51A), which is the target for azole antifungals. Infections caused by azole resistant Aspergillus species have led to inefficacy of azole antifungal drugs, leading to high fatality rates. However, resistant Aspergillus isolates have also been isolated from azole-naive patients. Global agricultural practices promote the use of azole fungicides to protect the crops from phytopathogens. The extensive use of azole fungicides has been linked to the development of resistance among Aspergillus species prevalent in the environment. The infections caused by these azole resistant Aspergillus species cannot be treated by the available azole drugs, in turn leading to high morbidity and mortality rates. Thus, knowledge of the environmental drivers and comprehending the genetic basis of fungal drug resistance evolution is pertinent, considering increasing numbers of patients with COVID-19 infections who are sensitive to opportunistic fungal infections. This review highlights the global magnitude and mechanisms of azole resistance in Aspergillus species, specifically focusing on environmental routes and resistance development.