Wang Bo, Zhang Feng-Wan, Wang Wei-Xiao, Zhao Yan-Yan, Sun Su-Yue, Yu Jin-Hong, Vitek Michael P, Li George F, Ma Rui, Wang Shiwei, Hu Zhiliang, Chen Wei
Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Department of Infectious Disease, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing, China.
Front Microbiol. 2022 Aug 23;13:934765. doi: 10.3389/fmicb.2022.934765. eCollection 2022.
The emergence of pandrug-resistant bacteria breaks through the last line of defense and raises fear among people of incurable infections. In the post-antibiotic era, the pharmaceutical field turns to seek non-conventional anti-infective agents. Antimicrobial peptides are considered a prospective solution to the crisis of antimicrobial resistance. In this study, we evaluated the antimicrobial efficiency of an ApoE mimetic peptide, COG1410, which has been confirmed to exhibit strong neural protective activity and immunomodulatory function. COG1410 showed potent antimicrobial activity against pandrug-resistant , even eliminating large inocula (10 CFU/ml) within 30 min. LC in PBS and 50% pooled human plasma was 2 μg/ml (1.4 μM) and 8 μg/ml (5.6 μM), respectively. Moreover, COG1410 exhibited biofilm inhibition and eradication activity, excellent stability in human plasma, and a low propensity to induce resistance. Although COG1410 easily entered bacterial cytoplasm and bound to DNA nonspecifically, the major mechanism of COG1410 killing was to disrupt the integrity of cell membrane and lead to leakage of cytoplasmic contents, without causing obvious pores on the cell surface or cell lysis. Additionally, transcriptome analysis showed that treatment with COG1410-enriched genes involved a series of oxidation-reduction processes. DCFH-DA probe detected an increased ROS level in the presence of COG1410, indicating ROS was another hit of this AMP. Furthermore, the action of COG1410 did not depend on the electronic interaction with the LPS layer, in contrast to polymyxin B. The strong synergistic interaction between COG1410 and polymyxin B dramatically reduced the working concentration of COG1410, expanding the safety window of the application. infection model showed that combined therapy of COG1410 and polymyxin B was capable of significantly rescuing the infected nematodes. Taken together, our study demonstrates that COG1410 is a promising drug candidate in the battle against pandrug-resistant .
泛耐药细菌的出现突破了最后一道防线，引发了人们对无法治愈感染的恐惧。在抗生素后时代，制药领域转而寻求非常规抗感染药物。抗菌肽被认为是解决抗菌耐药危机的一个有前景的方案。在本研究中，我们评估了一种载脂蛋白E模拟肽COG1410的抗菌效率，该肽已被证实具有强大的神经保护活性和免疫调节功能。COG1410对泛耐药菌显示出强大的抗菌活性，甚至能在30分钟内消除大量接种物（10 CFU/ml）。其在PBS和50%混合人血浆中的最低抑菌浓度分别为2 μg/ml（1.4 μM）和8 μg/ml（5.6 μM）。此外，COG1410表现出生物膜抑制和根除活性，在人血浆中稳定性良好，且诱导耐药的倾向较低。尽管COG1410很容易进入细菌细胞质并与DNA非特异性结合，但其主要杀菌机制是破坏细胞膜的完整性并导致细胞质内容物泄漏，而不会在细胞表面形成明显的孔或导致细胞裂解。此外，转录组分析表明，用富含COG1410的基因处理涉及一系列氧化还原过程。DCFH-DA探针检测到在COG1410存在下活性氧水平升高，表明活性氧是这种抗菌肽的另一个作用靶点。此外，与多粘菌素B不同，COG1410的作用不依赖于与脂多糖层的电子相互作用。COG1410与多粘菌素B之间强大的协同相互作用显著降低了COG1410的工作浓度，扩大了应用的安全窗口。感染模型表明，COG1410和多粘菌素B联合治疗能够显著挽救受感染的线虫。综上所述，我们的研究表明COG1410是对抗泛耐药菌的一种有前景的候选药物。
