Cocktail of CuO, ZnO, or CuZn Nanoparticles and Antibiotics for Combating Multidrug-Resistant Pseudomonas aeruginosa via Efflux Pump Inhibition,ACS Applied Nano Materials

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Cocktail of CuO, ZnO, or CuZn Nanoparticles and Antibiotics for Combating Multidrug-Resistant Pseudomonas aeruginosa via Efflux Pump Inhibition
ACS Applied Nano Materials ( IF 5.3 ) Pub Date : 2021-08-20 , DOI: 10.1021/acsanm.1c02208
Ioanna Eleftheriadou ₁ , Kleoniki Giannousi ₂ , Efthymia Protonotariou ₃ , Lemonia Skoura ₃ , Minas Arsenakis ₁ , Catherine Dendrinou-Samara ₂ , Afroditi Sivropoulou ₁

Affiliation

Multidrug resistant (MDR) bacteria have become an extremely serious public health concern. Bacteria can develop resistance through various mechanisms. Drug extrusion by the multidrug efflux pumps represents an important mechanism of antimicrobial resistance. Inhibitors of bacterial efflux pumps as adjuvants in antibacterial therapy are a reasonable and cost-effective pursuit since the shortage of antibiotics threatens global human health. Combined use of inorganic nanoparticles (NPs) with conventional antibiotics constitutes a promising alternative for fighting antibiotic resistance as NPs could restore the activity of the existing antibiotics. In the present study, the potential role of polyol-coated CuO, ZnO, and CuZn NPs as efflux pump inhibitors has been investigated against MDR clinical strains of Pseudomonas aeruginosa. The mode of action of the NPs was evaluated by studying their synergistic activity in combination with the antibiotics meropenem and ciprofloxacin, and their efflux inhibitory activity was studied by real-time fluorometry and a cartwheel assay. The results showed that the NPs act synergistically, in a concentration-dependent manner, with antibiotics known to be subject to efflux. Furthermore, the killing effect of the synergistic combinations over time was determined by time–kill studies. All the NPs at the lowest tested concentration enhanced the antibacterial activity of ciprofloxacin, as it was evidenced by both checkerboard and time–kill assays. Real-time fluorometric analyses revealed that NPs at sub-inhibitory concentrations promote the intracellular accumulation of ethidium bromide (EtBr). The EtBr agar cartwheel method showed that the NPs at the sub-minimum inhibitory concentration increased the fluorescence even at lower concentrations of EtBr, whereas in the absence of NPs, there was a much lower fluorescence. These results suggest that NPs may serve as potential sources of efflux pump inhibitors in order to tackle antimicrobial resistance.

中文翻译：

CuO、ZnO 或 CuZn 纳米颗粒和抗生素的混合物用于通过外排泵抑制对抗多药耐药铜绿假单胞菌

多重耐药 (MDR) 细菌已成为极其严重的公共卫生问题。细菌可以通过各种机制产生耐药性。多药外排泵的药物挤出代表了抗菌素耐药性的重要机制。由于抗生素短缺威胁全球人类健康，细菌外排泵抑制剂作为抗菌治疗的佐剂是合理且具有成本效益的追求。无机纳米粒子 (NPs) 与常规抗生素的结合使用构成了对抗抗生素耐药性的有希望的替代方法，因为 NPs 可以恢复现有抗生素的活性。在本研究中，多元醇包覆的 CuO、ZnO 和 CuZn NPs 作为外排泵抑制剂的潜在作用已针对 MDR 临床菌株进行了研究。铜绿假单胞菌. 通过研究它们与抗生素美罗培南和环丙沙星组合的协同活性来评估 NPs 的作用方式，并通过实时荧光测定法和车轮试验研究它们的外排抑制活性。结果表明，NPs 以浓度依赖的方式与已知会外排的抗生素协同作用。此外，协同组合随时间的杀灭效果由时间-杀灭研究确定。最低测试浓度下的所有 NPs 都增强了环丙沙星的抗菌活性，正如棋盘格和时间杀死试验所证明的那样。实时荧光分析显示亚抑制浓度的 NPs 促进了溴化乙锭 (EtBr) 的细胞内积累。EtBr 琼脂车轮法表明，即使在较低浓度的 EtBr 下，亚最低抑制浓度的 NPs 也会增加荧光，而在没有 NPs 的情况下，荧光要低得多。这些结果表明 NPs 可以作为外排泵抑制剂的潜在来源，以解决抗菌素耐药性问题。

更新日期：2021-09-24

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