Development of Antibiotic Adjuvants for Gram-Negative Bacteria

多重耐药(MDR)革兰氏阴性细菌感染对 公共卫生。粘菌素是一种多粘菌素抗生素，具有明显的肾脏毒性，现在被认为是最后一种抗生素。 求助于这些感染的治疗。随着粘菌素使用的卷土重来，对粘菌素具有抗药性的菌株 现在变得越来越普遍，特别是随着质粒携带的mcr-1基因的传播。为了抗击 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，以识别名为 抗生素佐剂，调节粘菌素对抗多药耐药革兰氏阴性病原体的活性。我们有 识别出可将粘菌素的最低抑菌浓度(MIC)降低2048倍的分子 粘菌素敏感和耐粘菌素细菌(鲍曼不动杆菌，铜绿假单胞菌， 肺炎克雷伯氏菌、大肠埃希菌)。机械学研究表明，我们的铅化合物结合在一起 鲍曼不动杆菌中的反应调节因子PmrA下调pmrCAB操纵子，逆转A类脂蛋白 修改。由于粘菌素的毒性是剂量依赖性的，这些化合物可能会降低 因此，对耐多药革兰氏阴性菌的治疗可以减轻毒性。在对粘菌素耐药的情况下 细菌，这种方法将有助于将MIC抑制在临床定义的耐药临界点以下 并再次使粘菌素疗法有效地治疗原本可能无效的感染。 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.