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

<i>Candida auris</i> 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, <i>C. auris</i> 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 <i>C. auris.</i> LNP also potentiates the antifungal activity of AmB against other medically important species of <i>Candida</i> and <i>Cryptococcus.</i> 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 <i>bc₁</i>). 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 <i>C. auris</i> in the kidneys. Our findings strongly advocate for a comprehensive evaluation of LNP as a cytochrome <i>bc₁</i> inhibitor for combating drug-resistant <i>C. auris</i> infections.