A Crucial Role for Ergosterol in Plasma Membrane Composition, Localisation, and Activity of Cdr1p and H+-ATPase in Candida albicans

Abstract

<i>Candida albicans</i> is an opportunistic fungal pathogen of humans. Treatment of <i>C. albicans</i> infections relies on azoles, which target the lanosterol 14α-demethylase (Erg11p) encoded by the <i>ERG11</i> gene. Our results show that targeted gene disruption of <i>ERG11</i> can result in resistance to ergosterol-dependent drugs (azoles and amphotericin B), auxotrophy and aerobically viable <i>erg11Δ/Δ</i> cells. Abnormal sterol deposition and lack of ergosterol in the <i>erg11Δ/Δ</i> strain leads to reduced plasma membrane (PM) fluidity, as well as dysfunction of the vacuolar and mitochondrial membranes, resulting respectively in defects in vacuole fusion and a reduced intracellular ATP level. The altered PM structure of the <i>erg11Δ/Δ</i> strain contributes to delocalisation of H⁺-ATPase and the Cdr1 efflux pump from the PM to vacuoles and, resulting in a decrease in PM potential (Δψ) and increased sensitivity to ergosterol-independent xenobiotics. This new insight into intracellular processes under Erg11p inhibition may lead to a better understanding of the indirect effects of azoles on <i>C. albicans</i> cells and the development of new treatment strategies for resistant infections.