Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA.
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 2759, USA.
ChemMedChem. 2020 Jan 17;15(2):210-218. doi: 10.1002/cmdc.201900560. Epub 2019 Dec 4.
Infections caused by multidrug-resistant (MDR) bacteria, particularly Gram-negative bacteria, are an escalating global health threat. Often clinicians are forced to administer the last-resort antibiotic colistin; however, colistin resistance is becoming increasingly prevalent, giving rise to the potential for a situation in which there are no treatment options for MDR Gram-negative infections. The development of adjuvants that circumvent bacterial resistance mechanisms is a promising orthogonal approach to the development of new antibiotics. We recently disclosed that the known IKK-β inhibitor IMD-0354 potently suppresses colistin resistance in several Gram-negative strains. In this study, we explore the structure-activity relationship (SAR) between the IMD-0354 scaffold and colistin resistance suppression, and identify several compounds with more potent activity than the parent against highly colistin-resistant strains of Acinetobacter baumannii and Klebsiella pneumoniae.
由耐多药（MDR）细菌引起的感染，特别是革兰氏阴性菌，是日益严重的全球健康威胁。通常，临床医生被迫使用最后一线抗生素粘菌素；然而，粘菌素耐药性越来越普遍，有可能出现针对 MDR 革兰氏阴性感染没有治疗选择的情况。开发克服细菌耐药机制的佐剂是开发新抗生素的一种很有前途的正交方法。我们最近披露，已知的 IKK-β抑制剂 IMD-0354 可有效抑制几种革兰氏阴性菌中的粘菌素耐药性。在这项研究中，我们探讨了 IMD-0354 支架与粘菌素耐药性抑制之间的构效关系（SAR），并确定了几种比母体化合物对高度耐粘菌素的鲍曼不动杆菌和肺炎克雷伯菌菌株具有更强活性的化合物。
