流出
大肠杆菌
普罗瓜尼
生物
抗菌剂
多重耐药
多药耐药相关蛋白
药理学
膜转运蛋白
抗药性
微生物学
化学
生物化学
运输机
恶性疟原虫
疟疾
ATP结合盒运输机
免疫学
基因
作者
Sabine Schuster,Martina Vavra,Winfried V Kern
出处
期刊:Microbial Drug Resistance
[Mary Ann Liebert]
日期:2022-10-17
卷期号:28 (12): 1065-1070
标识
DOI:10.1089/mdr.2022.0138
摘要
Efflux by resistance nodulation cell division transporters, such as AcrAB-TolC in Escherichia coli, substantially contributes to the development of Gram-negative multidrug resistance. Therefore, the finding of compounds that counteract efflux is an urgent goal in the fight against infectious diseases. Previously, an efflux inhibitory activity of the antimalarials mefloquine and artesunate was reported. In this study, we have investigated further antimalarials regarding efflux by AcrB, the pumping part of AcrAB-TolC, and their drug-enhancing potency in E. coli. We show that 10 of the 24 drugs tested are substrates of the multidrug efflux pump AcrB. Among them, tafenoquine and proguanil, when used at subinhibitory concentrations, caused an at least 4- and up to 24-fold enhancement in susceptibility to 6 and 14 antimicrobial agents, respectively. Both antimalarials are able to increase the intracellular accumulation of Hoechst 33342, with proguanil showing similar effectiveness as the efflux inhibitor 1-(1-naphthylmethyl)piperazine. In the case of proguanil, AcrB-dependent efflux inhibition could also be demonstrated in a real-time efflux assay. In addition to presenting new AcrB substrates, our study reveals two previously unknown efflux inhibitors among antimalarials. Particularly proguanil appears as a promising candidate and its chemical scaffold might be further optimized for repurposing as antimicrobial drug enhancer.
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