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CCCP Facilitates Aminoglycoside to Kill Late Stationary-Phase Escherichia coli by Elevating Hydroxyl Radical

文献类型： 外文期刊

作者： Li, Zhongyan 1 ; Wu, Ling 1 ; Huang, Zhijie 1 ; Lv, Boyan 1 ; Fu, Yajuan 2 ; Zhou, Lunjiang 3 ; Fu, Xinmiao 1 ;

作者机构： 1.Fujian Normal Univ, Prov Univ Key Lab Cellular Stress Response & Metab, Coll Life Sci, Fuzhou 350117, Fujian, Peoples R China

2.Fujian Normal Univ, Biomed Res Ctr South China, Fuzhou 350117, Fujian, Peoples R China

3.Fujian Acad Agr Sci, Inst Anim Husb & Vet Med, Fuzhou 350012, Fujian, Peoples R China

关键词： CCCP; aminoglycoside; antibiotic resistance; efflux pump; ROS; hydroxyl radical

期刊名称：ACS INFECTIOUS DISEASES （ 影响因子：5.3； 五年影响因子：5.1 ）

ISSN： 2373-8227

年卷期： 2023 年 9 卷 4 期

页码：

收录情况： SCI

摘要： Improving the efficacy of existing antibiotics is significant for combatting antibiotic resistance that poses a major threat to human health. Carbonyl cyanide m-chlorophenylhydrazine (CCCP), a well-known protonophore for dissipating proton motive force (PMF), has been widely used to block the PMFdependent uptake of aminoglycoside antibiotics and thus suppress aminoglycoside lethality. Here, we report that CCCP and its functional analog FCCP, but not other types of protonophores, unprecedently potentiate aminoglycosides (e.g., tobramycin and gentamicin) by 3-4 orders of magnitude killing of Escherichia coli, Staphylococcus aureus, Shigella flexneri, and Vibrio alginolyticus cells in stationary phase but not these cells in exponential phase nor other 12 bacterial species we examined. Overall, the effect of CCCP on aminoglycoside lethality undergoes a gradual transition from suppression against E. coli exponential-phase cells to potentiation against late stationary-phase cells, with the cell growth status and culture medium being crucial. Consistently, disturbance of the PMF by changing transmembrane proton gradient (Delta pH) or electric potential (Delta psi) also potentiates tobramycin. Nevertheless, CCCP neither increases the intracellular concentration of tobramycin nor decreases the MIC of the antibiotic, thus excluding that CCCP acts as an efflux pump inhibitor to potentiate aminoglycosides. Rather, we show that the combined treatment dramatically enhances the cellular level of hydroxyl radical under both aerobic and anaerobic culturing conditions, under which the antioxidant N-acetyl cysteine fully suppresses both hydroxyl radical accumulation and cell death. Together, these findings open a new avenue to develop certain protonophores as aminoglycoside adjuvants against pathogens in stationary phase and also illustrate an essential role of hydroxyl radical in aminoglycoside lethality regardless of aerobic respiration.

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