Reversal of Azole Resistance in Candida albicans by Sulfa Antibacterial Drugs

Eldesouky, Hassan E.; Mayhoub, Abdelrahman; Hazbun, Tony R.; Seleem, Mohamed N.

doi:10.1128/aac.00701-17

Cited by 55Antifungal resistance and susceptibilityFungal Plant Pathogen ControlFungal and yeast genetics research

Reversal of Azole Resistance in Candida albicans by Sulfa Antibacterial Drugs

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Eldesouky, Hassan E., Mayhoub, Abdelrahman, Hazbun, Tony R., Seleem, Mohamed N.·2018·Antimicrobial Agents and Chemotherapy

DOI 10.1128/aac.00701-17PMC PMC5826110

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Abstract

Invasive candidiasis presents an emerging global public health challenge due to the emergence of resistance to the frontline treatment options, such as fluconazole. Hence, the identification of other compounds capable of pairing with fluconazole and averting azole resistance would potentially prolong the clinical utility of this important group. In an effort to repurpose drugs in the field of antifungal drug discovery, we explored sulfa antibacterial drugs for the purpose of reversing azole resistance in Candida . In this study, we assembled and investigated a library of 21 sulfa antibacterial drugs for their ability to restore fluconazole sensitivity in Candida albicans . Surprisingly, the majority of assayed sulfa drugs (15 of 21) were found to exhibit synergistic relationships with fluconazole by checkerboard assay with fractional inhibitory concentration index (ΣFIC) values ranging from <0.0312 to 0.25. Remarkably, five sulfa drugs were able to reverse azole resistance in a clinically achievable range. The structure-activity relationships (SARs) of the amino benzene sulfonamide scaffold as antifungal agents were studied. We also identified the possible mechanism of the synergistic interaction of sulfa antibacterial drugs with azole antifungal drugs. Furthermore, the ability of sulfa antibacterial drugs to inhibit Candida biofilm by 40% in vitro was confirmed. In addition, the effects of sulfa-fluconazole combinations on Candida growth kinetics and efflux machinery were explored. Finally, using a Caenorhabditis elegans infection model, we demonstrated that the sulfa-fluconazole combination does possess potent antifungal activity in vivo , reducing Candida in infected worms by ∼50% compared to the control.

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The primary screen identified several drugs with known fluconazole chemosensitizing activities, including simvastatin, atorvastatin, lovastatin, artemisinin, amiodarone, sulfamethoxazole, doxycycline, nisoldipine, and tamoxifen.
“In addition and as expected, the primary screen identified several drugs with known fluconazole chemosensitizing activities, such as the cholesterol-lowering agents; simvastatin, atorvastatin, and lovastatin, artemisinin, amiodarone, sulfamethoxazole, doxycycline, and the calcineurin inhibitors nisoldipine and tamoxifen19–25.”
From Repurposing approach identifies pitavastatin as a potent azole chemosensitizing agent effective against azole-resistant Candida species (2020) · cites this paper as [21]
Combination therapy is an alternative approach to overcoming growing microbial infection resistance.
“Combination therapy is an alternative approach to overcoming the growing microbial infection resistance [23,24].”
From Lansoprazole interferes with fungal respiration and acts synergistically with amphotericin B against multidrug-resistant Candida auris (2024) · cites this paper as [24]

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Authors: Eldesouky, H. E., Mayhoub, A., Hazbun, T. R., & Seleem, M. N.
Affiliations: Purdue University West Lafayette (US)
Al-Azhar University (EG)
ORCID: Eldesouky, Hassan E.
Mayhoub, Abdelrahman
Hazbun, Tony R.
Seleem, Mohamed N.
Venue: Antimicrobial Agents and Chemotherapy
Publisher: American Society for Microbiology
Published: 2018-03
Volume: 62
Issue: 3
ISSN: 0066-4804 (ISSN-L)
1098-6596
DOI: 10.1128/aac.00701-17
PMC: PMC5826110
OpenAlex: W2775932866
Cited by: 55
References: 55
Citations by year: 2026: 1 · 2025: 3 · 2024: 10 · 2023: 7 · 2022: 7 · 2021: 5 · 2020: 13 · 2019: 6 · 2018: 3
FWCI: 4.63
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: journals.asm.org/non-commercial-tdm-license (tdm)
Locations: Antimicrobial Agents and Chemotherapy (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: HHS | NIH | National Institute of Allergy and Infectious Diseases (01AI130186)
Topics: Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
Keywords: Candida albicans, azole resistance, fluconazole, drug repurposing, antifungal synergy, invasive candidiasis, structure-activity relationship, Candida biofilms, efflux pumps, Caenorhabditis elegans infection model, combination therapy
MeSH terms: Animals, Anti-Bacterial Agents, Antifungal Agents, Azoles, Candida albicans, Microbial Sensitivity Tests, Structure-Activity Relationship, Fluconazole, Caenorhabditis elegans, Biofilms

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Reversal of Azole Resistance in Candida albicans by Sulfa Antibacterial Drugs

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