Development of Antibiotic Adjuvants for Gram-Negative Bacteria

多药耐药（MDR）革兰氏阴性细菌感染对人类的健康构成了巨大的持续挑战。 公共卫生粘菌素是一种多粘菌素类抗生素，具有明显的肾毒性，现在被认为是最后一种抗生素。 治疗这些感染的方法。随着粘菌素使用的复苏， 尤其是随着质粒携带的mcr-1基因的传播，现在变得更加普遍。打击 由于粘菌素耐药性的威胁越来越大，我们启动了一项研究计划，以确定小分子，称为 抗生素佐剂，其调节粘菌素对抗MDR革兰氏阴性病原体的活性。我们有 鉴定了将粘菌素的最低抑制浓度（MIC）降低高达2048倍的分子， 粘菌素敏感性和粘菌素抗性细菌（鲍氏不动杆菌，铜绿假单胞菌， 肺炎克雷伯氏菌和大肠杆菌）。机制研究表明我们的先导化合物 A.鲍曼不动杆菌，下调pmrCAB操纵子，并逆转脂质A 改性由于粘杆菌素毒性是剂量依赖性的，因此这些化合物降低用于治疗的剂量的潜力是有限的。 MDR革兰氏阴性菌的治疗可由此减轻毒性。在粘菌素耐药的情况下， 细菌，这种方法将有助于抑制MIC低于临床定义的耐药断点 并再次使粘菌素治疗有效地治疗感染，否则可能对这些感染无效， 抗生素

Multi-drug resistant (MDR) Gram-negative bacterial infections present an enormous ongoing challenge to public health. Colistin, a polymyxin antibiotic with noted renal toxicity, is now considered an antibiotic of last resort for the treatment of these infections. With the resurgence in colistin use, colistin-resistant isolates are now becoming more common, especially with the spread of the plasmid-borne mcr-1 gene. To combat the growing threat of colistin-resistance, we initiated a research program to identify small molecules, termed antibiotic adjuvants, that modulate the activity of colistin against MDR Gram-negative pathogens. We have identified molecules that lower the minimum inhibitory concentration (MIC) of colistin up to 2048-fold against both colistin-sensitive and colistin-resistant bacteria (Acinetobacter baumannii, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Escherichia coli). Mechanistic studies have shown that our lead compound binds the response regulator PmrA in A. baumannii, downregulates the pmrCAB operon, and reverses lipid A modification. As colistin toxicity is dose dependent, the potential of these compounds to lower dosages for the treatment of MDR Gram-negative bacteria could thereby mitigate toxicity. In the case of colistin-resistant bacteria, this approach would serve to suppress the MIC below the clinically defined breakpoint for resistance and again render colistin therapy efficacious to treat infections for which otherwise there may be no effective antibiotics.