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Potent Synergistic Interactions between Lopinavir and Azole Antifungal Drugs against Emerging Multidrug-Resistant Candida auris.

ABSTRACT: The limited therapeutic options and the recent emergence of multidrug-resistant Candida species present a significant challenge to human medicine and underscore the need for novel therapeutic approaches. Drug repurposing appears as a promising tool to augment the activity of current azole antifungals, especially against multidrug-resistant Candida auris In this study, we evaluated the fluconazole chemosensitization activities of 1,547 FDA-approved drugs and clinical molecules against azole-resistant C. auris This led to the discovery that lopinavir, an HIV protease inhibitor, is a potent agent capable of sensitizing C. auris to the effect of azole antifungals. At a therapeutically achievable concentration, lopinavir exhibited potent synergistic interactions with azole drugs, particularly with itraconazole against C. auris (fractional inhibitory concentration index [ΣFICI] ranged from 0.04 to 0.09). Additionally, the lopinavir/itraconazole combination enhanced the survival rate of C. auris-infected Caenorhabditis elegans by 90% and reduced the fungal burden in infected nematodes by 88.5% (P < 0.05) relative to that of the untreated control. Furthermore, lopinavir enhanced the antifungal activity of itraconazole against other medically important Candida species, including C. albicans, C. tropicalis, C. krusei, and C. parapsilosis Comparative transcriptomic profiling and mechanistic studies revealed that lopinavir was able to significantly interfere with the glucose permeation and ATP synthesis. This compromised the efflux ability of C. auris and consequently enhanced the susceptibility to azole drugs, as demonstrated by Nile red efflux assays. Altogether, these findings present lopinavir as a novel, potent, and broad-spectrum azole-chemosensitizing agent that warrants further investigation against recalcitrant Candida infections.

SUBMITTER: Eldesouky HE

PROVIDER: S-EPMC7927799 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Candida auris is a recently described pathogenic fungus that is causing invasive outbreaks on all continents. The fungus is of high concern given the numbers of multidrug-resistant strains that have been isolated in distinct sites across the globe. The fact that its diagnosis is still problematic suggests that the spreading of the pathogen remains underestimated. Notably, the molecular mechanisms of virulence and antifungal resistance employed by this new species are largely unknown. In the present work, we compared two clinical isolates of C. auris with distinct drug susceptibility profiles and a Candida albicans reference strain using a multi-omics approach. Our results show that, despite the distinct drug resistance profile, both C. auris isolates appear to be very similar, albeit with a few notable differences. However, compared to C. albicans both C. auris isolates have major differences regarding their carbon utilization and downstream lipid and protein content, suggesting a multifactorial mechanism of drug resistance. The molecular profile displayed by C. auris helps to explain the antifungal resistance and virulence phenotypes of this new emerging pathogen.IMPORTANCECandida auris was first described in Japan in 2009 and has now been the cause of significant outbreaks across the globe. The high number of isolates that are resistant to one or more antifungals, as well as the high mortality rates from patients with bloodstream infections, has attracted the attention of the medical mycology, infectious disease, and public health communities to this pathogenic fungus. In the current work, we performed a broad multi-omics approach on two clinical isolates isolated in New York, the most affected area in the United States and found that the omic profile of C. auris differs significantly from C. albicans In addition to our insights into C. auris carbon utilization and lipid and protein content, we believe that the availability of these data will enhance our ability to combat this rapidly emerging pathogenic yeast.

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Potent Synergistic Interactions between Lopinavir and Azole Antifungal Drugs against Emerging Multidrug-Resistant Candida auris.

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