Leveraging synthetic genetic array screening to identify therapeutic targets and inhibitors for combatting azole resistance in Candida glabrata

 Williams CC, Usher J. Microbiology Spectrum. 2025 Sep 2;13(9):e02522-24.

Fungal infections affect over 6.55 million individuals annually, with Candida glabrata (recently reclassified as Nakaseomyces glabratus) being the second most common cause of invasive candidiasis and candidemia, conditions that carry a high mortality rate of approximately 63.6%. C. glabrata exhibits significant genomic plasticity, enabling rapid adaptation to antifungal treatments. This ability is largely driven by gain-of-function (GOF) mutations in the CgPDR1 gene, which enhance the activity of efflux pumps and confer azole resistance. Over 80 unique CgPDR1 mutations have been identified, leading to diverse resistance profiles, from single-azole resistance to pan-azole resistance. These mutations not only increase resistance but also enhance the virulence of C. glabrata. To combat multi-drug-resistant (MDR) strains, which show resistance to azoles, echinocandins, and polyenes, novel multi-target therapeutic approaches are essential. This study employs synthetic genetic array (SGA) screening to explore the genetic interactions underlying CgPDR1+-mediated azole resistance, using the clinical allele R592S. By generating genome-wide double mutant strains, we identified gene deletions that cause synthetic sick (SS) and synthetic lethal (SL) interactions, providing potential therapeutic targets. In silico screening identified inhibitors of these targets, and one was validated in vitro. Our findings support the potential of SGA screening to identify antifungal adjuvants that can slow the emergence of azole resistance in C. glabrata. 

Read the full paper here