Center for Research Innovation and Biomedical Informatics, Faculty of Medical Technology, Mahidol University, Salaya, Nakhon Pathom, Thailand.
Department of Clinical Microbiology and Applied Technology, Faculty of Medical Technology, Mahidol University, Bangkok, Thailand.
PLoS One. 2023 Nov 16;18(11):e0294287. doi: 10.1371/journal.pone.0294287. eCollection 2023.
Drug-resistant Enterobacterales infections are a great health concern due to the lack of effective treatments. Consequently, finding novel antimicrobials or combining therapies becomes a crucial approach in addressing this problem. BP203 and MAP-0403 J-2, novel antimicrobial peptides, have exhibited effectiveness against Gram-negative bacteria. In this study, we assessed the in vitro antibacterial activity of BP203 and MAP-0403 J-2, along with their synergistic interaction with conventional antibiotics including colistin, rifampicin, chloramphenicol, ceftazidime, meropenem, and ciprofloxacin against colistin-resistant Escherichia coli and Klebsiella pneumoniae clinical isolates. The minimal inhibitory concentrations (MIC) of BP203 and MAP-0403 J-2 against tested E. coli isolates were 2-16 and 8-32 μg/mL, respectively. However, for the majority of K. pneumoniae isolates, the MIC of BP203 and MAP-0403 J-2 were >128 μg/mL. Notably, our results demonstrated a synergistic effect when combining BP203 with rifampicin, meropenem, or chloramphenicol, primarily observed in most K. pneumoniae isolates. In contrast, no synergism was evident between BP203 and colistin, chloramphenicol, ceftazidime, rifampicin, or ciprofloxacin when tested against all E. coli isolates. Furthermore, synergistic effects between MAP-0403 J-2 and rifampicin, ceftazidime or colistin were observed against the majority of E. coli isolates. Similarly, the combined effect of MAP-0403 J-2 with rifampicin or chloramphenicol was synergistic in the majority of K. pneumoniae isolates. Importantly, these peptides displayed the stability at high temperatures, across a wide range of pH values, in specific serum concentrations and under physiological salt conditions. Both peptides also showed no significant hemolysis and cytotoxicity against mammalian cells. Our findings suggested that BP203 and MAP-0403 J-2 are promising candidates against colistin-resistant E. coli. Meanwhile, the synergism of these peptides and certain antibiotics could be of great therapeutic value as antimicrobial drugs against infections caused by colistin-resistant E. coli and K. pneumoniae.
由于缺乏有效的治疗方法，耐多药肠杆菌科感染是一个严重的健康问题。因此，寻找新的抗菌药物或联合治疗成为解决这一问题的关键方法。BP203 和 MAP-0403 J-2 是两种新型抗菌肽，已被证明对革兰氏阴性菌有效。在这项研究中，我们评估了 BP203 和 MAP-0403 J-2 的体外抗菌活性，以及它们与多粘菌素、利福平、氯霉素、头孢他啶、美罗培南和环丙沙星等常规抗生素联合使用对多粘菌素耐药大肠埃希菌和肺炎克雷伯菌临床分离株的协同作用。BP203 和 MAP-0403 J-2 对测试的大肠埃希菌分离株的最小抑菌浓度（MIC）分别为 2-16 和 8-32 μg/mL。然而，对于大多数肺炎克雷伯菌分离株，BP203 和 MAP-0403 J-2 的 MIC 均>128 μg/mL。值得注意的是，当与利福平、美罗培南或氯霉素联合使用时，我们的结果显示出协同作用，主要在大多数肺炎克雷伯菌分离株中观察到。相比之下，当测试所有大肠埃希菌分离株时，BP203 与多粘菌素、氯霉素、头孢他啶、利福平或环丙沙星之间没有协同作用。此外，MAP-0403 J-2 与利福平、头孢他啶或多粘菌素对大多数大肠埃希菌分离株表现出协同作用。同样，MAP-0403 J-2 与利福平或氯霉素联合使用的协同作用在大多数肺炎克雷伯菌分离株中也是如此。重要的是，这些肽在高温、宽 pH 值范围、特定血清浓度和生理盐条件下均表现出稳定性。两种肽对哺乳动物细胞也没有明显的溶血和细胞毒性。我们的研究结果表明，BP203 和 MAP-0403 J-2 是治疗多粘菌素耐药大肠埃希菌的有前途的候选药物。同时，这些肽与某些抗生素的协同作用可能具有很大的治疗价值，可作为治疗多粘菌素耐药大肠埃希菌和肺炎克雷伯菌感染的抗菌药物。
