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:10.1101/2023.05.01.538946

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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

bioRxiv

Cold Spring Harbor Laboratory

05/01/2023

DOI: 10.1101/2023.05.01.538946

PMCID: PMC10187223

PMID: 37205554

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https://doi.org/10.1101/2023.05.01.538946View

Preprint (Author's original)This preprint has not been evaluated by subject experts through peer review. Preprints may undergo extensive changes and/or become peer-reviewed journal articles. Open Access

Abstract

Multidrug resistance (MDR) transporters such as ATP Binding Cassette (ABC) and Major Facilitator Superfamily (MFS) 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 multidrug resistance transporters. Here, we show that the improved C. albicans activity is because fluphenazine induces its own resistance by triggering expression of 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 represents a unique example of a medicinal chemistry-based conversion of chemical scaffold from MDR-sensitive to MDR-resistant and, hence, active against fungi that have developed resistance to clinically used antifungals such as the azoles.

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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: Preprint
Publication Details: bioRxiv
DOI: 10.1101/2023.05.01.538946
PMID: 37205554
PMCID: PMC10187223
Publisher: Cold Spring Harbor Laboratory
Language: English
Date posted: 05/01/2023
Academic Unit: Molecular Physiology and Biophysics; Microbiology and Immunology; Stead Family Department of Pediatrics; Infectious Disease (Pediatrics)
Record Identifier: 9984413076702771

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