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.

多重耐药 (MDR) 革兰氏阴性菌是一种紧迫且迅速传播的威胁人类健康的疾病，治疗选择有限。以前，我们发现了一种新的 [1,2,5] 恶二唑并 [3,4- b ] 含吡嗪化合物 ( 1 )，它可以选择性地使多种 MDR 革兰氏阴性细菌对粘菌素重新敏感，粘菌素是最后的手段之一抗生素。在此，我们报告了化合物1的结构-活性关系研究，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对多种 MDR 细菌有效。这些结果证明这些化合物是一类新的 RMA，并且可以进一步开发为治疗剂。