Synergistic Effect of Fluconazole and Calcium Channel Blockers against Resistant Candida albicans
Open accessAbstract
Candidiasis has increased significantly recently that threatens patients with low immunity. However, the number of antifungal drugs on the market is limited in comparison to the number of available antibacterial drugs. This fact, coupled with the increased frequency of fungal resistance, makes it necessary to develop new therapeutic strategies. Combination drug therapy is one of the most widely used and effective strategy to alleviate this problem. In this paper, we were aimed to evaluate the combined antifungal effects of four CCBs (calcium channel blockers), amlodipine (AML), nifedipine (NIF), benidipine (BEN) and flunarizine (FNZ) with fluconazole against C. albicans by checkerboard and time-killing method. In addition, we determined gene (CCH1, MID1, CNA1, CNB1, YVC1, CDR1, CDR2 and MDR1) expression by quantitative PCR and investigated the efflux pump activity of resistant candida albicans by rhodamine 6G assay to reveal the potential mechanisms. Finally, we concluded that there was a synergy when fluconazole combined with the four tested CCBs against resistant strains, with fractional inhibitory concentration index (FICI) <0.5, but no interaction against sensitive strains (FICI = 0.56 ~ 2). The mechanism studies revealed that fluconazole plus amlodipine caused down-regulating of CNA1, CNB1 (encoding calcineurin) and YVC1 (encoding calcium channel protein in vacuole membrane).
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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 [19]
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Synergy, antagonism, and what the chequerboard puts between them
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BindingDB Entry 50002345: Emerging New Targets for the Treatment of Resistant Fungal Infections.
BindingDB (2020) · UC San Diego · doi:10.7270/q26112x4
- Authors
- Liu, S., Yue, L., Gu, W., Li, X., Zhang, L., & Sun, S.
- Affiliations
- Shandong University (CN)
- Taishan Medical University (CN)
- Corresponding author
- Sun, Shujuan
- Venue
- PLOS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2016-03-17
- Volume
- 11
- Issue
- 3
- Pages
- e0150859
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC4795682
- OpenAlex
- W2334493659
- Cited by
- 87
- References
- 41
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 3 · 2023: 7 · 2022: 4 · 2021: 9 · 2020: 16 · 2019: 11 · 2018: 9 · 2017: 14 · 2016: 7
- FWCI
- 12.61
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- Shandong University
- Department of Science and Technology of Shandong Province (2013GSF11848)
- Natural Science Foundation of Shandong Province (ZR2011HL049)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
- Keywords
- Candida albicans, fluconazole, calcium channel blockers, amlodipine, nifedipine, benidipine, flunarizine, antifungal synergy, antifungal resistance, efflux pumps, CDR1, CDR2, MDR1, calcineurin, candidiasis, combination antifungal therapy
- MeSH terms
- Antifungal Agents, Calcium Channel Blockers, Candida albicans, Candidiasis, Drug Synergism, Fungal Proteins, Humans, Microbial Sensitivity Tests, Fluconazole, Gene Expression Regulation, Fungal, Drug Resistance, Fungal
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