Reversal of efflux mediated antifungal resistance underlies synergistic activity of two monoterpenes with fluconazole

Ahmad, Aijaz; Khan, Amber; Manzoor, Nikhat

doi:10.1016/j.ejps.2012.09.016

Cited by 110 publications

(73 citation statements)

References 32 publications

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“…Hoechst 33342 and R6G are two fluorescent dyes that accumulate into cells and are then pumped out by the ABC superfamily as they are substrates for these efflux pumps [16]. Our results demonstrated that the mean intracellular concentration of these dyes in various Candida spp exposed to thymol and carvacrol were significantly higher than in the untreated controls [17]. These two natural compounds inhibit drug efflux pumps in Candida, decreasing efflux activity and hence increasing intracellular dye accumulation.…”

mentioning

confidence: 60%

Reversing Antifungal Drug Resistance using Natural Plant Products

Manzoor¹

2015

Transcriptomics

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mentioning

confidence: 60%

Reversing Antifungal Drug Resistance using Natural Plant Products

Manzoor¹

2015

Transcriptomics

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“…Thymol, for instance, not only inhibits fluconazole efflux but also inhibits CDR1 and MDR1 transcription (37). However, qPCR assays revealed that compounds 1 and 2, the most promising lead inhibitors, did not modulate the transcription of CDR1, CDR2, MDR1, and ERG11 to a relevant extent in any of the three resistant isolates.…”

Section: Discussionmentioning

confidence: 96%

“…Gray bars indicate the percent Nile red accumulation relative to the sensitive control strain AD/pABC3 in the presence of PBS (pH 7.2), which was set to 100% of Nile red-preloaded AD/CaMDR1 cells incubated in the presence of buffer only (PBS, pH 7.2), buffer including the vehicle control of 0.5% DMSO, or buffer plus 100 M concentrations of compounds 1 to 5 (34,35,37,38, and 40 g/ml, respectively), dissolved in DMSO, as indicated. The data represent the means Ϯ the standard errors from three independent experiments (*, P Ͻ 0.05 compared to AD/CaMDR1).…”

Section: Figmentioning

confidence: 99%

Synthetic Organotellurium Compounds Sensitize Drug-Resistant Candida albicans Clinical Isolates to Fluconazole

Sá

Toledo

Gonçalves

et al. 2017

Antimicrob Agents Chemother

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Invasive Candida albicans infections are a serious health threat for immunocompromised individuals. Fluconazole is most commonly used to treat these infections, but resistance due to the overexpression of multidrug efflux pumps is of grave concern. This study evaluated the ability of five synthetic organotellurium compounds to reverse the fluconazole resistance of C. albicans clinical isolates. Compounds 1 to 4, at Ͻ10 g/ml, ameliorated the fluconazole resistance of Saccharomyces cerevisiae strains overexpressing the major C. albicans multidrug efflux pumps Cdr1p and Mdr1p, whereas compound 5 only sensitized Mdr1p-overexpressing strains to fluconazole. Compounds 1 to 4 also inhibited efflux of the fluorescent substrate rhodamine 6G and the ATPase activity of Cdr1p, whereas all five of compounds 1 to 5 inhibited Nile red efflux by Mdr1p. Interestingly, all five compounds demonstrated synergy with fluconazole against efflux pump-overexpressing fluconazoleresistant C. albicans clinical isolates, isolate 95-142 overexpressing CDR1 and CDR2, isolate 96-25 overexpressing MDR1 and ERG11, and isolate 12-99 overexpressing CDR1, CDR2, MDR1, and ERG11. Overall, organotellurium compounds 1 and 2 were the most promising fluconazole chemosensitizers of fluconazole-resistant C. albicans isolates. Our data suggest that these novel organotellurium compounds inhibit pump efflux by two very important and distinct families of fungal multidrug efflux pumps: the ATP-binding cassette transporter Cdr1p and the major facilitator superfamily transporter Mdr1p.

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“…Considering the importance of major antifungal transport pumps, one focus of recent research has been to understand the relationship between this synergism and drug transport pumps. Functional activities of drug transport pumps have traditionally been assayed with Rh6G, a known fluorescent substrate of several drug transport pumps responsible for multidrug resistance in yeasts and a FLC alternate (Ahmad et al, 2013). We employed this Rh6G-based assay to determine whether the synergistic effects were correlated with the inhibition of drug transport pumps.…”

Section: Discussionmentioning

confidence: 99%

Ambroxol Hydrochloride Combined with Fluconazole Reverses the Resistance of Candida albicans to Fluconazole

Liu

Zhao

Huang

et al. 2017

Front. Cell. Infect. Microbiol.

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In this study, we found that ambroxol hydrochloride (128 μg/mL) exhibits synergistic antifungal effects in combination with fluconazole (2 μg/mL) against resistant planktonic Candida albicans (C. albicans) cells. This combination also exhibited synergistic effects against resistant C. albicans biofilms in different stages (4, 8, and 12 h) according to the microdilution method. In vitro data were further confirmed by the success of this combination in treating Galleria mellonella infected by resistant C. albicans. With respect to the synergistic mechanism, our result revealed that ambroxol hydrochloride has an effect on the drug transporters of resistant C. albicans, increasing the uptake and decreasing the efflux of rhodamine 6G, a fluorescent alternate of fluconazole. This is the first study to investigate the in vitro and in vivo antifungal effects, as well as the possible synergistic mechanism of ambroxol hydrochloride in combination with fluconazole against resistant C. albicans. The results show the potential role for this drug combination as a therapeutic alternative to treat resistant C. albicans and provide insights into the development of antifungal targets and new antifungal agents.

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Reversal of efflux mediated antifungal resistance underlies synergistic activity of two monoterpenes with fluconazole

Cited by 110 publications

References 32 publications

Reversing Antifungal Drug Resistance using Natural Plant Products

Reversing Antifungal Drug Resistance using Natural Plant Products

Synthetic Organotellurium Compounds Sensitize Drug-Resistant Candida albicans Clinical Isolates to Fluconazole

Ambroxol Hydrochloride Combined with Fluconazole Reverses the Resistance of Candida albicans to Fluconazole

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