Drug repurposing and SAR - a powerful combination in combating Candida auris.

Abstract

Fungal infections pose a significant and increasing threat to human health but the current armoury of antifungal drugs is inadequate. In order to find novel drugs and drug targets we conducted a phenotypic screen against Candida species using compounds of the Medicines for Malaria Venture (MMV) Pathogen box. Several compounds showed antifungal activity against C. auris and MMV022478 was selected for structure-activity relationship (SAR) and mode-of-action (MOA) studies. Chemical modifications of MMV022478 greatly improved the efficacy against C. auris but also reduced cytotoxic effects towards mammalian cell lines. Long-term evolution experiments in the presence of MMV022478 and subsequent genome sequencing revealed genes involved in the adaptation to antifungal drug exposure in C. auris. SNP analysis together with thermal proteome profiling provided insight into the MOA of MMV022478.  

Biography

Claudia Simm completed her PhD in Biochemistry at the Martin-Luther University in Halle, Germany followed by a postdoc position at the University of Madison, Wisconsin. Her main research focused on heavy metal detoxification and distribution in yeast. In 2006 she joined the start-up company Viamet Pharmaceuticals to conduct antifungal targeting zinc and iron homeostasis. After relocating to the UK in 2011 she worked on drug discovery for Cystic Fibrosis at Novartis before venturing into the field of neurodegenerative diseases at Chronos. She returned to academia in 2016 and joined the lab of Robin May at the University of Birmingham where she worked on antifungal drug development funded through an industry collaboration with F2G, Manchester. In 2019 she moved to Melbourne and joined Ana Traven’s lab at Monash University where she has set up Candida auris as a research organism and is running the drug discovery side of the lab.