A crucial role for ergosterol in plasma membrane composition, localisation, and activity of Cdr1p and H+-ATPase in Candida albicans

Abstract

Candida albicans is an opportunistic fungal pathogen of humans. Treatment of C. albicans infections relies on azoles, which target the lanosterol 14α-demethylase (Erg11p) encoded by the ERG11 gene. Our results show that targeted gene disruption of ERG11 can result in resistance to ergosterol-dependent drugs (azoles and amphotericin B), auxotrophy and aerobically viable erg11∆/∆ cells. Abnormal sterol deposition and lack of ergosterol in the erg11∆/∆ 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 erg11∆/∆ 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 (∆ψ) 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 C. albicans cells and the development of new treatment strategies for resistant infections.