Overexpression of Staphylococcus aureus efflux pumps is commonly associated with antibiotic resistance, causing conventional antibiotics to be unsuccessful in combating multidrug-resistant bacterial infections. Reducing the activity of the efflux pump is an urgently required to tackle this problem. Here, we found that plantaricin A (PlnA), an antimicrobial peptide derived from Lactobacillus plantarum, had a synergistic effect with ciprofloxacin (CIP), reducing the IC₉₀ of CIP by eight times. Subsequently, changes in membrane permeability, membrane potential, and reactive oxygen species (ROS) were determined; changes that did not explain the synergistic effect were previously observed. Ethidium bromide intake and efflux experiments showed that PlnA inhibited the function of the efflux pump by binding it and altering the structure of MepA, NorA, and LmrS. Then, a series of PlnA mutants were designed to explore the underlying mechanism; they showed that the charge and foaming of PlnA were the predominant factors affecting the structure of NorA. In a skin wound infection model, PlnA significantly reduced the dose of CIP, relieved inflammation, and promoted wound healing, indicating that PlnA and CIP synergy persisted in vivo. Overall, PlnA reduced the use of CIP for combination therapy, and allowing the continued used of CIP to kill MDR S. aureus. Multidrug-resistant Staphylococcus aureus threatens our life as a tenacious pathogen, which causes infections in hospitals, communities and animal husbandry. Various studies have showed that efflux pump inhibitors (EPIs) have been considered potential therapeutic agents for rejuvenating the activity of antibiotics. Unfortunately, small molecule EPIs exhibit several side effects that limit their use for clinical application. The present study showed a new EPI (plantaricin A) produced by Lactobacillus plantarum, which has low cytotoxicity and haemolysis and powerful inhibitory activity on efflux pumps. Therefore, it helps the design of new EPIs and controls the infection of MDR S. aureus.

中文翻译：

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Plantaricin A 通过抑制外排泵逆转耐多药金黄色葡萄球菌对环丙沙星的耐药性

金黄色葡萄球菌外排泵的过度表达通常与抗生素耐药性有关，导致传统抗生素无法成功对抗多重耐药细菌感染。减少外排泵的活动是解决这个问题的迫切需要。在这里，我们发现植物乳杆菌 (Lactobacillus plantarum ) 的抗菌肽植物霉素 A (PlnA)与环丙沙星 (CIP) 具有协同作用，降低 IC ₉₀CIP 的 8 倍。随后，测定了膜通透性、膜电位和活性氧 (ROS) 的变化；之前观察到了不能解释协同效应的变化。溴化乙锭摄入和流出实验表明，PlnA 通过结合它并改变 MepA、NorA 和 LmrS 的结构来抑制流出泵的功能。然后，设计了一系列 PlnA 突变体来探索其潜在机制；他们表明，PlnA的充注和起泡是影响NorA结构的主要因素。在皮肤伤口感染模型中，PlnA 显着降低了 CIP 的剂量，缓解炎症，促进伤口愈合，表明 PlnA 和 CIP 协同作用在体内持续存在。总体而言，PlnA 减少了 CIP 在联合治疗中的使用，金黄色葡萄球菌。耐多药金黄色葡萄球菌作为一种顽固的病原体威胁着我们的生命，它会导致医院、社区和畜牧业的感染。各种研究表明，外排泵抑制剂 (EPI) 已被认为是恢复抗生素活性的潜在治疗剂。不幸的是，小分子 EPI 表现出一些限制其临床应用的副作用。本研究展示了一种由植物乳杆菌产生的新的EPI（Plantaricin A） ，它具有低细胞毒性和溶血作用，并且对外排泵具有强大的抑制活性。因此，它有助于设计新的 EPI 并控制 MDR S. aureus的感染。