Resistance of ERG24 sterol C-14 reductase to heterocyclic amine antifungals.

Abstract

There is an urgent need for a wider range of antifungals in medicine and agriculture and for their dual use in both contexts to be minimised. As new modes of action may incur unforeseen side-effects, existing groups of antifungals which have had limited use may be attractive options for development. Here, we report mutations in ERG24 sterol C-14 reductase which cause resistance of wheat powdery mildew to heterocyclic amine fungicides with a phenylpropyl chain, and confirm their effect by single-base editing in yeast. The resistance mutations have at most small effects on mitotic fitness measured by yeast growth parameters. Predictive protein modelling indicates that phenylpropylamines likely obstruct the sterol substrate's access to the catalytic site, and thus act as competitive inhibitors, but do not bind directly to the catalytic residues. This information may support structure-guided development of new antifungals targetting ERG24 as alternatives to the widely-used ERG11 inhibitors.