The sphingolipid inhibitor myriocin increases susceptibility of Candida auris to amphotericin B

Abstract

The emerging human fungal pathogen Candida auris can cause of hospital outbreaks by transmission between patients and / or medical care staff. It is known for a fast adaption to environmental stress and antifungal treatment. Besides resistance to fluconazole in most isolates, C. auris frequently shows limited susceptibility to echinocandins and even to amphotericin B. Therefore, multidrug resistance (MDR) is frequently found in clinical isolates, leading to a need for new therapeutic targets and compounds. One of those targets could be sphingolipids which are an integral part of the cell membrane and are important for membrane fluidity and the formation of lipid rafts. Here, we show that myriocin-mediated inhibition of the de novo sphingolipid biosynthesis caused severe growth defects in C. auris. Sublethal myriocin concentrations increase fungal susceptibility to amphotericin B and anidulafungin. While the effect is limited for anidulafungin, even isolates that show phenotypic resistance to amphotericin B became susceptible in presence of myriocin. A large-scale screening of 59 clinical isolates validated these initial results and showed that inhibition of the de novo sphingolipid biosynthesis increases C. auris susceptibility to amphotericin B. These observations open new options for future therapeutic strategies and illustrate that sphingolipids might play a pivotal role for the ability of C. auris to develop resistance against amphotericin B.