Resistance to antifungals that target CYP51

Abstract

Fungal diseases are an increasing global burden. Fungi are now recognised to kill more people annually than malaria, whilst in agriculture, fungi threaten crop yields and food security. Azole resistance, mediated by several mechanisms including point mutations in the target enzyme (CYP51), is increasing through selection pressure as a result of widespread use of triazole fungicides in agriculture and triazole antifungal drugs in the clinic. Mutations similar to those seen in clinical isolates as long ago as the 1990s in Candida albicans and later in Aspergillus fumigatus have been identified in agriculturally important fungal species and also wider combinations of point mutations. Recently, evidence that mutations originate in the field and now appear in clinical infections has been suggested. This situation is likely to increase in prevalence as triazole fungicide use continues to rise. Here, we review the progress made in understanding azole resistance found amongst clinically and agriculturally important fungal species focussing on resistance mechanisms associated with CYP51. Biochemical characterisation of wild-type and mutant CYP51 enzymes through ligand binding studies and azole IC50 determinations is an important tool for understanding azole susceptibility and can be used in conjunction with microbiological methods (MIC50 values), molecular biological studies (site-directed mutagenesis) and protein modelling studies to inform future antifungal development with increased specificity for the target enzyme over the host homologue.

Structural and Functional Elucidation of Yeast Lanosterol 14α-Demethylase in Complex with Agrochemical Antifungals

“…tritici ( M . graminicola ) [31] as well as the human pathogens Candida albicans and Aspergillus fumigatus [5, 19, 32]. Mutation of tyrosine 140 (Y140, S .…”

“…albicans Darlington strain [33], and TR46/Y121F/T289A in A . fumigatus CYP51A, which is thought to have arisen due to agricultural use of azoles [5, 6], confers resistance to VCZ. Other mutations have been associated with reduced susceptibility to azole agrochemicals.…”

“…[5]. Azoles are routinely used to treat diseases caused by phytopathogenic fungi including eyespot disease and powdery mildew in wheat and barley, black rust, headblight and septoria leaf blotch in wheat, leaf scald in cereals, leaf spot in sugar beet, powdery mildew on grapes, black sigatoka in bananas, apple scab, and mold on citrus fruit as well as the production of toxins.…”

Azole fungicides - understanding resistance mechanisms in agricultural fungal pathogens

“…This was superseded by the double mutation Y137F‐S542T in the early 2000s and resulted in increased resistance to the same compound. However, as triadimenol is no longer used to treat septoria leaf blotch and has been replaced by newer azoles, the Y137F and Y137F‐S542T mutations are now rarely seen …”

Exploiting new knowledge of Candidal infection for future antifungal combat

“…Presumably, still many health professionals prescribe antifungals, and patients use over‐the‐counter antifungals, on assumption of mucosal candidosis based on symptoms or unspecific clinical presentation but without a confirmed diagnosis of candidosis. The environment is exposed extensively to azoles as they are used as fungicides in seed, postharvest crops, woods, textile and toiletries and excreted by humans and animals during azole treatment (Parker et al , ).…”