Broad sensitivity ofCandida aurisstrains to quinolones and mechanisms of resistance

Abstract

The fungal pathogenCandida aurisrepresents a severe threat to hospitalized patients. Its resistance to multiple classes of antifungal drugs and ability to spread and resist decontamination in health-care settings make it especially dangerous. We screened 1,990 clinically approved and late-stage investigational compounds for the potential to be repurposed as antifungal drugs targetingC. aurisand narrowed our focus to five FDA-approved compounds with inhibitory concentrations under 10 μM forC. aurisand significantly lower toxicity to three human cell lines. These compounds, some of which had been previously identified in independent screens, include three dihalogenated 8-hydroxyquinolines: broxyquinoline, chloroxine, and clioquinol. A subsequent structure-activity study of 32 quinoline derivatives found that 8-hydroxyquinolines, especially those dihalogenated at the C5 and C7 positions, were the most effective inhibitors ofC. auris. To pursue these compounds further, we exposedC. auristo clioquinol in an extended experimental evolution study and found thatC. aurisdeveloped only 2- to 5-fold resistance to the compound. DNA sequencing of resistant strains and subsequent verification by directed mutation in naive strains revealed that resistance was due to mutations in the transcriptional regulatorCAP1(causing upregulation of the drug transporterMDR1) and in the drug transporterCDR1. These mutations had only modest effects on resistance to traditional antifungal agents, and theCDR1mutation renderedC. aurismore sensitive to posaconazole. This observation raises the possibility that a combination treatment involving an 8-hydroxyquinoline and posaconazole might preventC. aurisfrom developing resistance to this established antifungal agent.