Department of Chemistry, University of Colorado, Boulder, CO 80309, USA.
Department of Chemistry, University of Colorado, Boulder, CO 80309, USA.
Bioorg Med Chem Lett. 2022 Sep 15;72:128878. doi: 10.1016/j.bmcl.2022.128878. Epub 2022 Jul 3.
Multidrug-resistant (MDR) Gram-negative bacteria are an urgent and rapidly spreading threat to human health with limited treatment options. Previously, we discovered a novel [1,2,5]oxadiazolo[3,4-b]pyrazine-containing compound (1) that selectively re-sensitized a variety of MDR Gram-negative bacteria to colistin, one of the last-resort antibiotic. Herein, we report the structure-activity relationship studies of compound 1 that led to the discovery of several more potent and/or less toxic resistance-modifying agents (RMAs). Further evaluation of these RMAs showed that they were effective in a wide range of MDR bacteria. These results demonstrated these compounds as a novel class of RMAs and may be further developed as therapeutic agents.
多药耐药（MDR）革兰氏阴性菌对人类健康构成了紧迫且迅速蔓延的威胁，而可用的治疗选择却十分有限。此前，我们发现了一种新型[1,2,5]恶二唑并[3,4-b]吡嗪类化合物（1），它可选择性地使多种多药耐药革兰氏阴性菌重新对粘菌素（一种最后手段的抗生素）敏感。在此，我们报告了化合物 1 的构效关系研究，这些研究导致发现了几种更有效和/或毒性更低的耐药调节剂（RMA）。对这些 RMA 的进一步评估表明，它们在多种多药耐药菌中均有效。这些结果表明这些化合物为一类新型 RMA，并且可能被进一步开发为治疗剂。
