Broad sensitivity ofCandida aurisstrains to quinolones and mechanisms of resistance

Abstract

AbstractThe 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.Abstract ImportanceThe rapidly emerging fungal pathogenCandida aurisrepresents a growing threat to hospitalized patients, in part due to frequent resistance to multiple classes of antifungal drugs. We identify a class of compounds, the dihalogenated hydroxyquinolines, with broad fungistatic ability against a diverse collection of 13 strains ofC. auris. Although this compound has been identified in previous screens, we extended the analysis by showing thatC. aurisdeveloped only modest 2- to 5-fold increases in resistance to this class of compounds despite long-term exposure; a noticeable difference from the 30- to 500- fold increases in resistance reported for similar studies with commonly used antifungal drugs. We also identify the mutations underlying the resistance. These results suggest that the dihalogenated hydroxyquinolines are working inside the fungal cell and should be developed further to combatC. aurisand other fungal pathogens.TweetLohse and colleagues characterize a class of compounds that inhibit the fungal pathogenC. auris. Unlike many other antifungal drugs,C. aurisdoes not readily develop resistance to this class of compounds.