Journal article
Derivatives of the Antimalarial Drug Mefloquine Are Broad-Spectrum Antifungal Molecules with Activity against Drug-Resistant Clinical Isolates
Antimicrobial agents and chemotherapy, Vol.64(3), e02331-19
03/01/2020
DOI: 10.1128/AAC.02331-19
PMCID: PMC7038245
PMID: 31907188
Abstract
The antifungal pharmacopeia is critically small, particularly in light of the recent emergence of multidrug-resistant pathogens, such as Candida auris. Here, we report that derivatives of the antimalarial drug mefloquine have broad-spectrum antifungal activity against pathogenic yeasts and molds. In addition, the mefloquine derivatives have activity against clinical isolates that are resistant to one or more of the three classes of antifungal drugs currently used to treat invasive fungal infections, indicating that they have a novel mechanism of action. Importantly, the in vitro toxicity profiles obtained using human cell lines indicated that the toxicity profiles of the mefloquine derivatives are very similar to those of the parent mefloquine, despite being up to 64-fold more active against fungal cells. In addition to direct antifungal activity, subinhibitory concentrations of the mefloquine derivatives inhibited the expression of virulence traits, including filamentation in Candida albicans and capsule formation/melanization in Cryptococcus neoformans. Mode/mechanism-of-action experiments indicated that the mefloquine derivatives interfere with both mitochondrial and vacuolar function as part of a multitarget mechanism of action. The broad-spectrum scope of activity, blood-brain barrier penetration, and large number of previously synthesized analogs available combine to support the further optimization and development of the antifungal activity of this general class of drug-like molecules.
Details
- Title: Subtitle
- Derivatives of the Antimalarial Drug Mefloquine Are Broad-Spectrum Antifungal Molecules with Activity against Drug-Resistant Clinical Isolates
- Creators
- Marhiah C. Montoya - University of RochesterSarah Beattie - Roy J. and Lucille A. Carver College of MedicineKathryn M. Alden - Roy J. and Lucille A. Carver College of MedicineDamian J. Krysan - Roy J. and Lucille A. Carver College of Medicine
- Resource Type
- Journal article
- Publication Details
- Antimicrobial agents and chemotherapy, Vol.64(3), e02331-19
- Publisher
- Amer Soc Microbiology
- DOI
- 10.1128/AAC.02331-19
- PMID
- 31907188
- PMCID
- PMC7038245
- ISSN
- 0066-4804
- eISSN
- 1098-6596
- Number of pages
- 18
- Grant note
- BWF1014095 / Burroughs Wellcome Fund TL1TR002000; UL1TR002001 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA 1R21AI125094 / NIAID; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID)
- Language
- English
- Date published
- 03/01/2020
- Academic Unit
- Microbiology and Immunology; Stead Family Department of Pediatrics; Infectious Disease (Pediatrics)
- Record Identifier
- 9984297318402771
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