Abstract
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).
Highlights
Candidiasis is one of the most important human opportunistic fungal infections, which threatens peoples living with immune system compromise, including solid organ transplant, AIDS or cancer patients, and hematopoietic stem cell transplant recipients
3.1 Calcium channel blockers tested significantly increased the sensitivity of fluconazole to resistant Candida albicans
The results interpreted by ΔE method demonstrated to be strong synergistic with very high percentages of interactions ranging from 964.71% to 1866.19% (Fig 1)
Summary
Candidiasis is one of the most important human opportunistic fungal infections, which threatens peoples living with immune system compromise, including solid organ transplant, AIDS or cancer patients, and hematopoietic stem cell transplant recipients. Despite the availability of several other classes of antifungal drugs (Polyenes, Pyrimidines, Echinocandins), inherent toxicity, cost of care, and emergence of resistance remain major problems in clinic, and the available antifungal agents are still limited [7]. These problems point to an urgent and unmet need for the development of new antifungal agents or searching for new antifungal approaches. Some non-antifungal agents with action of disturbing calcium homeostasis may become the potential candidates to combine with FLC to fight against fungal infections [11,12,15,25,26]. In order to identify whether the combinations could reverse one of the most common resistant mechanism of increased drug efflux, we conducted rhodamine 6G assays to investigate activity of efflux pump protein and RT-PCR to determine gene expression of CDR1, CDR2 and MDR1 [28]
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