The emergence of plasmid-encoded colistin resistance mechanisms, MCR-1, a phosphoethanolamine transferase, rendered colistin ineffective as last resort antibiotic against severe infections caused by clinical Gram-negative bacterial pathogens. Through screening FDA-approved drug library, we identified two structurally similar compounds, namely cetylpyridinium chloride (CET) and domiphen bromide (DOM), which potentiated colistin activity in both colistin-resistant and susceptible Enterobacterales. These compounds were found to insert their long carbon chain to a hydrophobic pocket of bacterial phosphoethanolamine transferases including MCR-1, competitively blocking the binding of lipid A tail for substrate recognition and modification, resulting in the increase of bacterial sensitivity to colistin. In addition, these compounds were also found to dissipate bacterial membrane potential leading to the increase of bacterial sensitivity to colistin. Importantly, combinational use of DOM with colistin exhibited remarkable protection of test animals against infections by colistin-resistant bacteria in both mouse thigh infection and sepsis models. For mice infected by colistin-susceptible bacteria, the combinational use of DOM and colistin enable us to use lower dose of colistin to for efficient treatment. These properties render DOM excellent adjuvant candidates that help transform colistin into a highly potent antimicrobial agent for treatment of colistin-resistant Gram-negative bacterial infections and allowed us to use of a much lower dosage of colistin to reduce its toxicity against colistin-susceptible bacterial infection such as carbapenem-resistant Enterobacterales.

中文翻译：

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重新利用氯化西吡啶和溴化多米芬作为磷酸乙醇胺转移酶抑制剂来对抗粘菌素耐药性肠杆菌


质粒编码的粘菌素耐药机制MCR-1（一种磷酸乙醇胺转移酶）的出现，使得粘菌素作为对抗临床革兰氏阴性细菌病原体引起的严重感染的最后手段抗生素无效。通过筛选 FDA 批准的药物库，我们鉴定了两种结构相似的化合物，即氯化十六烷基吡啶 (CET) 和溴化多米芬 (DOM)，它们在耐粘菌素和敏感肠杆菌中增强了粘菌素活性。这些化合物被发现将其长碳链插入细菌磷酸乙醇胺转移酶（包括MCR-1）的疏水口袋中，竞争性地阻断脂质A尾部的结合以进行底物识别和修饰，从而增加细菌对粘菌素的敏感性。此外，这些化合物还被发现可以消散细菌膜电位，导致细菌对粘菌素的敏感性增加。重要的是，在小鼠大腿感染和脓毒症模型中，DOM 与粘菌素的联合使用对测试动物免受粘菌素耐药细菌的感染表现出显着的保护作用。对于粘菌素敏感细菌感染的小鼠，DOM和粘菌素的联合使用使我们能够使用较低剂量的粘菌素来进行有效的治疗。这些特性使 DOM 成为优秀的候选佐剂，有助于将粘菌素转化为高效抗菌剂，用于治疗粘菌素耐药的革兰氏阴性细菌感染，并使我们能够使用低得多的粘菌素剂量来降低其对粘菌素敏感细菌感染的毒性例如耐碳青霉烯类肠杆菌。