Fluphenazine antagonizes with fluconazole but synergizes with amphotericin B in the treatment of candidiasis

Lu, Yangyu; Zhou, Zhixiang; Mo, Longyi; Guo, Qiang; Peng, Xian; Hu, Tao; Zhou, Xuedong; Ren, Biao; Xu, Xin

doi:10.1007/s00253-019-09960-3

Cited by 10 publications

(7 citation statements)

References 53 publications

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“…Consistent with previous work (9,10), both fluphenazine and CWHM-974 are antagonistic with fluconazole in C. albicans by checkerboard analysis (Table 1). Interestingly, both fluphenazine and CWHM-974 strongly inducing the expression of CDR1 (Fig.…”

Section: Fluphenazine and Cwhm-974 Inducesupporting

confidence: 91%

“…Thus, the induction of antagonism by fluphenazine and CWHM-974 can be explained by activation of the Tac1-Cdr1 axis. Phenothiazines have been shown to inhibit efflux pump function in other settings (10), raising the possibility that the increased anti-C. albicans activity of CWHM-974 may be due to its ability to inhibit Cdr1. If that were the case, then CWHM-974 would induce CDR1 but there would be no antagonism with fluconazole.…”

Section: Fluphenazine and Cwhm-974 Inducementioning

confidence: 99%

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CWHM-974 is a fluphenazine derivative with improved antifungal activity againstCandida albicansdue to reduced susceptibility to multidrug transporter-mediated resistance mechanisms

Miron-Ocampo

Beattie

Guin

et al. 2023

Preprint

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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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Section: Fluphenazine and Cwhm-974 Inducesupporting

confidence: 91%

Section: Fluphenazine and Cwhm-974 Inducementioning

confidence: 99%

CWHM-974 is a fluphenazine derivative with improved antifungal activity againstCandida albicansdue to reduced susceptibility to multidrug transporter-mediated resistance mechanisms

Miron-Ocampo

Beattie

Guin

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…The combination of fluphenazine and fluconazole is antagonistic against C. albicans ( 11 , 12 ), presumably by induction of CDR1/2 , although that has not been experimentally confirmed. To test this hypothesis further, we first asked whether the combination of fluconazole and fluphenazine induced CDR1 in an additive or synergistic manner.…”

Section: Resultsmentioning

confidence: 99%

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

Miron-Ocampo,

Beattie,

Guin

et al. 2023

Antimicrob Agents Chemother

View full text Add to dashboard Cite

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.

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“…577 The continued development of these engineering strategies will facilitate widespread applications of EAMs in various bio-electrochemical systems, including e-skin, 578,579 medical diagnostics, 580,581 nanomaterials synthesis, 561 bioelectricitydriven human-computer interaction technologies, MFCs for wastewater treatment and pollutions detection, microfluidic biochips, and electroactive biofilm-based hydrovoltaic technologies. 582…”

Section: Novel Synthetic Biology Technology For Enhancing Outward Eetmentioning

confidence: 99%

Engineering extracellular electron transfer pathways of electroactive microorganisms by synthetic biology for energy and chemicals production

Zhang,

Li,

Liu

et al. 2024

Chem. Soc. Rev.

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Fluphenazine antagonizes with fluconazole but synergizes with amphotericin B in the treatment of candidiasis

Cited by 10 publications

References 53 publications

CWHM-974 is a fluphenazine derivative with improved antifungal activity againstCandida albicansdue to reduced susceptibility to multidrug transporter-mediated resistance mechanisms

CWHM-974 is a fluphenazine derivative with improved antifungal activity againstCandida albicansdue to reduced susceptibility to multidrug transporter-mediated resistance mechanisms

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

Engineering extracellular electron transfer pathways of electroactive microorganisms by synthetic biology for energy and chemicals production

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