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

Summary

Candida glabrata is a dangerous fungus causing serious infections that is becoming resistant to antifungal drugs. Researchers used a genetic screening technique to find genes that interact with drug resistance mutations and identified methotrexate (a drug already used for arthritis) as a potential partner for fluconazole treatment. When combined, these drugs work better together against resistant strains of the fungus, offering hope for treating these stubborn infections.

Background

Candida glabrata is the second most common cause of invasive candidiasis with approximately 63.6% mortality rate. The pathogen exhibits significant genomic plasticity and rapidly develops resistance to antifungal treatments, particularly azoles, through gain-of-function mutations in the CgPDR1 gene that enhance efflux pump activity.

Objective

This study employed synthetic genetic array screening to identify genetic interactions underlying CgPDR1-mediated azole resistance using the clinical allele R592S. The research aimed to identify potential therapeutic targets and inhibitors that could slow the emergence of azole resistance in multidrug-resistant C. glabrata strains.

Results

SGA screening identified five genes (HEK2, PDR8, GCN5, STE2, and STE12) common to all CgPDR1 mutations. Methotrexate was identified as a potential inhibitor of CgGCN5 and demonstrated synergistic effects with fluconazole against C. glabrata, particularly against strains carrying various CgPDR1 mutations.

Conclusion

The findings support the utility of SGA screening for identifying antifungal adjuvants that can slow azole resistance emergence in C. glabrata. The combination of methotrexate with fluconazole shows promise as a multi-target therapeutic approach, with GCN5 representing an attractive target for adjunctive antifungal therapy.
  • Published in:Microbiology Spectrum,
  • Study Type:Experimental Research Study,
  • Source: 40787998
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