CWHM-974 is a fluphenazine derivative with improved antifungal activity against Candida albicans due to reduced susceptibility to multidrug transporter-mediated resistance mechanisms

Aracely Miron-Ocampo; Sarah R Beattie; Soumitra Guin; Thomas Conway; Marvin J Meyers; W Scott Moye-Rowley; Damian J Krysan

doi:10.1128/aac.00567-23

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CWHM-974 is a fluphenazine derivative with improved antifungal activity against Candida albicans due to reduced susceptibility to multidrug transporter-mediated resistance mechanisms

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CWHM-974 is a fluphenazine derivative with improved antifungal activity against Candida albicans due to reduced susceptibility to multidrug transporter-mediated resistance mechanisms

Aracely Miron-Ocampo, Sarah R Beattie, Soumitra Guin, Thomas Conway, Marvin J Meyers, W Scott Moye-Rowley and Damian J Krysan

Antimicrobial agents and chemotherapy, Vol.67(10), e0056723

10/18/2023

DOI: 10.1128/aac.00567-23

PMCID: PMC10583685

PMID: 37702508

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Abstract

Multidrug resistance (MDR) transporters such as ATP-Binding Cassette (ABC) and Major Facilitator Superfamily proteins are important mediators of antifungal drug resistance, particularly with respect to azole class drugs. Consequently, identifying molecules that are not susceptible to this mechanism of resistance is an important goal for new antifungal drug discovery. As part of a project to optimize the antifungal activity of clinically used phenothiazines, we synthesized a fluphenazine derivative (CWHM-974) with 8-fold higher activity against Candida spp. compared to the fluphenazine and with activity against Candida spp. with reduced fluconazole susceptibility due to increased MDR transporters. Here, we show that the improved C. albicans activity is because fluphenazine induces its own resistance by triggering expression of Candida drug resistance (CDR) transporters while CWHM-974 induces expression but does not appear to be a substrate for the transporters or is insensitive to their effects through other mechanisms. We also found that fluphenazine and CWHM-974 are antagonistic with fluconazole in C. albicans but not in C. glabrata, despite inducing CDR1 expression to high levels. Overall, CWHM-974 is one of the few examples of a molecule in which relatively small structural modifications significantly reduced susceptibility to multidrug transporter-mediated resistance.

Details

Title: Subtitle: CWHM-974 is a fluphenazine derivative with improved antifungal activity against Candida albicans due to reduced susceptibility to multidrug transporter-mediated resistance mechanisms
Creators: Aracely Miron-Ocampo - University of Iowa
Sarah R Beattie - University of Iowa
Soumitra Guin - Saint Louis University
Thomas Conway - University of Iowa
Marvin J Meyers - Saint Louis University
W Scott Moye-Rowley - University of Iowa
Damian J Krysan - University of Iowa
Resource Type: Journal article
Publication Details: Antimicrobial agents and chemotherapy, Vol.67(10), e0056723
DOI: 10.1128/aac.00567-23
PMID: 37702508
PMCID: PMC10583685
NLM abbreviation: Antimicrob Agents Chemother
eISSN: 1098-6596
Grant note: DOI: 10.13039/100000060, name: HHS | NIH | National Institute of Allergy and Infectious Diseases, award: R21AI164578; DOI: 10.13039/100000060, name: HHS | NIH | National Institute of Allergy and Infectious Diseases, award: F32AI145160; DOI: 10.13039/100000060, name: HHS | NIH | National Institute of Allergy and Infectious Diseases, award: R01AI52494
Language: English
Electronic publication date: 09/13/2023
Date published: 10/18/2023
Academic Unit: Molecular Physiology and Biophysics; Microbiology and Immunology; Stead Family Department of Pediatrics; Infectious Disease (Pediatrics)
Record Identifier: 9984463128802771

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