title: Combination of fluconazole with non-antifungal agents: a promising approach to cope with resistant Candida albicans infections and insight into new antifungal agent discovery.
abstract: The past decades have witnessed a dramatic increase in invasive fungal infections, especially candidiasis. Despite the development of more effective new antifungal agents, fluconazole (FLC) is still widely used in the clinic because of its efficacy and low toxicity. However, as the number of patients treated with FLC has increased, FLC-resistant Candida albicans isolates emerge more frequently. In addition, biofilm-associated infections are commonly encountered and their resistance poses a great challenge to antifungal treatment. Various approaches have been proposed to increase the susceptibility of C. albicans to FLC in order to cope with treatment failures, among which is the combination of FLC with different classes of non-antifungal agents such as antibacterials, calcineurin inhibitors, heat shock protein 90 inhibitors, calcium homeostasis regulators and traditional Chinese medicine drugs. Interestingly, many of these combinations showed synergistic effects against C. albicans, especially resistant strains. The main mechanisms of these synergistic effects appear to be increasing the permeability of the membrane, reducing the efflux of antifungal drugs, interfering with intracellular ion homeostasis, inhibiting the activity of proteins and enzymes required for fungal survival, and inhibiting biofilm formation. These modes of action and the antifungal mechanisms of various compounds referenced in this paper highlight the idea that the reversal of fungal resistance can be achieved through various mechanisms. Studies examining drug interactions will hopefully provide new approaches against antifungal drug resistance as well as insight into antifungal agent discovery.
authors: School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong Province, People's Republic of China.
authors: Shuyuan
authors: S
authors: Liu
authors: Department of Cardiology, Qianfoshan Hospital Affiliated to Shandong University, Jinan 250014, Shandong Province, People's Republic of China.
authors: Yinglong
authors: Y
authors: Hou
authors: Department of Pharmacy, Zhejiang Provincial Taizhou Hospital, Linhai 317000, Zhejiang Province, People's Republic of China.
authors: Xu
authors: X
authors: Chen
authors: School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong Province, People's Republic of China.
authors: Yuan
authors: Y
authors: Gao
authors: School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong Province, People's Republic of China.
authors: Hui
authors: H
authors: Li
authors: Department of Pharmacy, Qianfoshan Hospital Affiliated to Shandong University, Jinan 250014, Shandong Province, People's Republic of China. Electronic address: sunshujuan888@163.com.
authors: Shujuan
authors: S
authors: Sun
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects* / Q000302:isolation & purification; D002177:Candidiasis / Q000382:microbiology; D055808:Drug Discovery / Q000379:methods*; D004347:Drug Interactions; D025141:Drug Resistance, Fungal / Q000187:drug effects*; D015725:Fluconazole / Q000494:pharmacology*; D006801:Humans
chemical_list: D000935:Antifungal Agents; D015725:Fluconazole
keywords: Antifungal resistance; Combination; Fluconazole; New approaches to antifungal therapy