Lansoprazole interferes with fungal respiration and acts synergistically with amphotericin B against multidrug-resistant 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, possesses extraordinary resistant profiles aga...

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Published in:Emerging microbes & infections 2024-12, Vol.13 (1), p.2322649-2322649
Main Authors: Salama, Ehab A, Elgammal, Yehia, Wijeratne, Aruna, Lanman, Nadia A, Utturkar, Sagar M, Farhangian, Atena, Li, Jianing, Meunier, Brigitte, Hazbun, Tony R, Seleem, Mohamed N
Format: Article
Language:English
Subjects:
Amphotericin B - pharmacology
Animals
Antifungal Agents - pharmacology
C. auris
Candida auris
Candidiasis
Cytochrome
cytochrome bc1
Cytochromes
Drug Resistance and Novel Antimicrobial Agents
fungal respiration
Human health and pathology
Infectious diseases
Lansoprazole
Lansoprazole - pharmacology
Life Sciences
metabolites
Mice
Microbiology and Parasitology
Mycology
Pharmaceutical sciences
Pharmacology
PISA analysis
Respiration
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Summary: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, 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 LNP also potentiates the antifungal activity of AmB against other medically important species of and 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 ). 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 in the kidneys. Our findings strongly advocate for a comprehensive evaluation of LNP as a cytochrome inhibitor for combating drug-resistant infections.
ISSN:2222-1751
2222-1751
DOI:10.1080/22221751.2024.2322649