Abstract：
Nontuberculous mycobacteria (NTM), which include the Mycobacterium avium complex, are classified as difficult-to-treat pathogens due to their ability to quickly develop drug resistance against the most common antibiotics used to treat NTM infections. The overexpression of efflux pumps (EPs) was demonstrated to be a key mechanism of clarithromycin (CLA) resistance in NTM. Therefore, in this work, 24 compounds from an in-house library, characterized by chemical diversity, were tested as potential NTM EP inhibitors (EPIs) against Mycobacterium smegmatis mc2 155 and M. avium clinical isolates. Based on the acquired results, 12 novel analogs of the best derivatives 1b and 7b were designed and synthesized to improve the NTM EP inhibition activity. Among the second set of compounds, 13b emerged as the most potent NTM EPI. At a concentration of 4 µg/mL, it reduced the CLA minimum inhibitory concentration by 16-fold against the clinical isolate M. avium 2373 overexpressing EPs as primary mechanism of CLA resistance.
摘要：
非结核分枝杆菌（NTM），其中包括鸟分枝杆菌复合体，被归类为难以治疗的病原体，因为它们能够快速产生对用于治疗NTM感染的最常见抗生素的耐药性。外排泵（EP）的过表达被证明是NTM中克拉霉素（CLA）耐药的关键机制。因此,在这项工作中，来自内部图书馆的24种化合物，以化学多样性为特征，被测试为针对耻垢分枝杆菌mc2.155和鸟分枝杆菌临床分离株的潜在NTMEP抑制剂（EPIs）。根据获得的结果，设计并合成了12种最佳衍生物1b和7b的新型类似物以提高NTMEP抑制活性。在第二组化合物中，13b作为最有效的NTMEPI出现。浓度为4μg/mL时，它将CLA的最低抑制浓度降低了16倍，以对抗过表达EP的临床分离株M.avium2373作为CLA抗性的主要机制。
