Department of Chemistry & Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA.
Department of Microbial Pathogenesis, University of Maryland-Baltimore, Baltimore, MD 21201, USA.
Bioorg Med Chem. 2019 May 1;27(9):1776-1788. doi: 10.1016/j.bmc.2019.03.019. Epub 2019 Mar 8.
The last three decades have seen a dwindling number of novel antibiotic classes approved for clinical use and a concurrent increase in levels of antibiotic resistance, necessitating alternative methods to combat the rise of multi-drug resistant bacteria. A promising strategy employs antibiotic adjuvants, non-toxic molecules that disarm antibiotic resistance. When co-dosed with antibiotics, these compounds restore antibiotic efficacy in drug-resistant strains. Herein we identify derivatives of tryptamine, a ubiquitous biochemical scaffold containing an indole ring system, capable of disarming colistin resistance in the Gram-negative bacterial pathogens Acinetobacter baumannii, Klebsiella pneumoniae, and Escherichia coli while having no inherent bacterial toxicity. Resistance was overcome in strains carrying endogenous chromosomally-encoded colistin resistance machinery, as well as resistance conferred by the mobile colistin resistance-1 (mcr-1) plasmid-borne gene. These compounds restore a colistin minimum inhibitory concentration (MIC) below the Clinical & Laboratory Sciences Institute (CLSI) breakpoint in all resistant strains.
过去三十年，新批准用于临床使用的抗生素种类逐渐减少，而抗生素耐药性水平却在不断上升，因此需要寻找替代方法来对抗多药耐药菌的出现。一种有前途的策略是使用抗生素佐剂，即能够消除抗生素耐药性的无毒分子。当与抗生素联合使用时，这些化合物可以恢复耐药菌株对抗生素的疗效。在此，我们发现了色胺的衍生物，色胺是一种普遍存在的生化支架，含有吲哚环系统，能够消除革兰氏阴性细菌病原体鲍曼不动杆菌、肺炎克雷伯菌和大肠杆菌中的多粘菌素耐药性，而本身没有固有细菌毒性。这些化合物克服了携带内源性染色体编码多粘菌素耐药机制的菌株以及由移动性多粘菌素耐药基因 1 (mcr-1)质粒携带的耐药性。这些化合物使所有耐药菌株的多粘菌素最低抑菌浓度（MIC）恢复到临床和实验室科学研究所（CLSI）的 breakpoint 以下。
