Lee Hyeju, Kim Byeongkwon, Kim Minju, Yoo Seoyeong, Lee Jinkyeong, Hwang Eunha, Kim Yangmee
Department of Bioscience and Biotechnology, Konkuk University, Seoul 05029, Republic of Korea.
Center for Research Equipment, Korea Basic Science Institute, Cheongju 28119, Republic of Korea.
Pharmaceutics. 2023 Jun 16;15(6):1752. doi: 10.3390/pharmaceutics15061752.
The spread of colistin-resistant bacteria is a serious threat to public health. As an alternative to traditional antibiotics, antimicrobial peptides (AMPs) show promise against multidrug resistance. In this study, we investigated the activity of the insect AMP cecropin A ( cecropin) against colistin-resistant bacteria. cecropin exhibited significant antibacterial and antibiofilm activities against colistin-resistant (ColREC) with low cytotoxicity against mammalian cells in vitro. Results of permeabilization of the ColREC outer membrane as monitored through 1-N-phenylnaphthylamine uptake, scanning electron microscopy, lipopolysaccharide (LPS) neutralization, and LPS-binding interaction revealed that cecropin manifested antibacterial activity by targeting the outer membrane of with strong interaction with LPS. cecropin specifically targeted toll-like receptor 4 (TLR4) and showed anti-inflammatory activities with a significant reduction of inflammatory cytokines in macrophages stimulated with either LPS or ColREC via blockade of TLR4-mediated inflammatory signaling. Moreover, cecropin exhibited anti-septic effects in an LPS-induced endotoxemia mouse model, confirming its LPS-neutralizing activity, immunosuppressive effect, and recovery of organ damage in vivo. These findings demonstrate that cecropin exerts strong antimicrobial activities against ColREC and could serve as a foundation for the development of AMP therapeutics.
耐黏菌素细菌的传播对公众健康构成严重威胁。作为传统抗生素的替代品，抗菌肽（AMPs）显示出对抗多重耐药性的潜力。在本研究中，我们调查了昆虫抗菌肽天蚕素A（cecropin）对耐黏菌素细菌的活性。cecropin在体外对耐黏菌素细菌（ColREC）表现出显著的抗菌和抗生物膜活性，且对哺乳动物细胞的细胞毒性较低。通过1-N-苯基萘胺摄取、扫描电子显微镜、脂多糖（LPS）中和以及LPS结合相互作用监测ColREC外膜通透性的结果表明，cecropin通过靶向其外膜并与LPS强烈相互作用而表现出抗菌活性。cecropin特异性靶向Toll样受体4（TLR4），并通过阻断TLR4介导的炎症信号传导，在LPS或ColREC刺激的巨噬细胞中显著降低炎症细胞因子，从而显示出抗炎活性。此外，cecropin在LPS诱导的内毒素血症小鼠模型中表现出抗脓毒症作用，证实了其在体内的LPS中和活性、免疫抑制作用以及对器官损伤的恢复作用。这些发现表明，cecropin对ColREC具有强大的抗菌活性，可为抗菌肽疗法的开发奠定基础。
