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      Derivatives of the Antimalarial Drug Mefloquine Are Broad-Spectrum Antifungal Molecules with Activity against Drug-Resistant Clinical Isolates

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          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.

          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.

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          Author and article information

          Journal
          Antimicrob Agents Chemother
          Antimicrob. Agents Chemother
          aac
          aac
          AAC
          Antimicrobial Agents and Chemotherapy
          American Society for Microbiology (1752 N St., N.W., Washington, DC )
          0066-4804
          1098-6596
          21 February 2020
          March 2020
          6 January 2020
          : 64
          : 3
          : e02331-19
          Affiliations
          [a ] Clinical and Translational Science Institute, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
          [b ] Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA
          [c ] Department of Microbiology, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA
          Author notes
          Address correspondence to Damian J. Krysan, damian-krysan@ 123456uiowa.edu .

          Citation Montoya MC, Beattie S, Alden KM, Krysan DJ. 2020. Derivatives of the antimalarial drug mefloquine are broad-spectrum antifungal molecules with activity against drug-resistant clinical isolates. Antimicrob Agents Chemother 64:e02331-19. https://doi.org/10.1128/AAC.02331-19.

          Article
          PMC7038245 PMC7038245 7038245 02331-19
          10.1128/AAC.02331-19
          7038245
          31907188
          b27c1b02-972b-404b-a056-1541606b3e31
          Copyright © 2020 American Society for Microbiology.

          All Rights Reserved.

          History
          : 21 November 2019
          : 16 December 2019
          : 20 December 2019
          Page count
          supplementary-material: 1, Figures: 9, Tables: 2, Equations: 0, References: 58, Pages: 18, Words: 10667
          Funding
          Funded by: HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID), https://doi.org/10.13039/100000060;
          Award ID: 1R21AI125094
          Award Recipient :
          Categories
          Experimental Therapeutics
          Custom metadata
          March 2020

          antifungal agents, Cryptococcus ,antifungal, Candida auris , Aspergillus ,mefloquine, Candida ,repurposing, Cryptococcus neoformans

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