Lansoprazole interferes with fungal respiration and acts synergistically with amphotericin B against multidrug-resistant Candida auris

ABSTRACT

Candida auris has emerged as a problematic fungal pathogen associated with high morbidity and mortality. Amphotericin B (AmB) is the most effective antifungal used to treat invasive fungal candidiasis, with resistance rarely observed among clinical isolates. However, C. auris possesses extraordinary resistant profiles against all available antifungal drugs, including AmB. In our pursuit of potential solutions, we screened a panel of 727 FDA-approved drugs. We identified the proton pump inhibitor lansoprazole (LNP) as a potent enhancer of AmB’s activity against C. auris. LNP also potentiates the antifungal activity of AmB against other medically important species of Candida and Cryptococcus. Our investigations into the mechanism of action unveiled that LNP metabolite(s) interact with a crucial target in the mitochondrial respiratory chain (complex III, known as cytochrome bc₁). This interaction increases oxidative stress within fungal cells. Our results demonstrated the critical role of an active respiratory function in the antifungal activity of LNP. Most importantly, LNP restored the efficacy of AmB in an immunocompromised mouse model, resulting in a 1.7-log (∼98%) CFU reduction in the burden of C. auris in the kidneys. Our findings strongly advocate for a comprehensive evaluation of LNP as a cytochrome bc₁ inhibitor for combating drug-resistant C. auris infections.

KEYWORDS:

• Lansoprazole
• metabolites
• PISA analysis
• C. auris
• fungal respiration
• cytochrome bc₁
• In vivo mouse model

Acknowledgments

We acknowledge the CDC and BEI Resources, which provided the fungal isolates used in this study. The NIH Clinical Collections 1 & 2 were provided by the National Institutes of Health (NIH). S. cerevisiae AD1-9 strain was kindly provided by M. Ghislain, UCL, Belgium. We also acknowledge the support of the Collaborative Core for Cancer Bioinformatics from the Purdue University Institute for Cancer Research (PU-ICR), NIH grants R01AI141439, P30 CA023168 and the Walther Cancer Foundation. We also thank Dr. Hassan Eldesouky for his help with the library screening.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Ethical approval for animal experiment

The Virginia Tech Institutional Animal Care and Use Committee approved the use of animals in these experiments.

Data availability

All RNA-seq data are available in the NCBI database (Gene Expression Omnibus [GEO]) under the accession number GSE244094.

Additional information

Funding

This work was supported by National Institutes of Health: [Grant numbers R01AI141439 and P30 CA023168].