Department of Biomedical Science, Graduate School, Chosun University, Gwangju, 61452, Republic of Korea.
Department of Biomedical Science, Graduate School, Chosun University, Gwangju, 61452, Republic of Korea; Department of Microbiology, School of Medicine, Chosun University, Gwangju, 61452, Republic of Korea.
Eur J Med Chem. 2019 Nov 15;182:111623. doi: 10.1016/j.ejmech.2019.111623. Epub 2019 Aug 13.
Fowlicidin-1 (Fowl-1), a cathelicidin expressed in chicken intestine, is known to have both antimicrobial and anti-inflammatory properties. However, its pharmaceutical development has been ultimately compromised by its high host cytotoxicity. In this study, a series of N- and C-terminal-truncated 19-meric Fowl-1 peptides were synthesized. Among these truncated peptides, Fowl-1 (8-26) exhibited broad-spectrum antimicrobial activity without human erythrocyte cytotoxicity while reducing anti-inflammatory activity. Further, Fowl-1 (8-26)-WRK was designed via Thr→Trp, Ile→Arg, and Asn→Lys substitutions in Fowl-1 (8-26) to exhibit more amphipathicity. The results revealed that it exhibited both antimicrobial and anti-inflammatory properties. This study also demonstrated that the inhibitory activity of Fowl-1 (8-26)-WRK against LPS-induced inflammation was mainly due to the binding of LPS to the peptide. Interestingly, compared with human cathelicidin LL-37 and melittin, Fowl-1 (8-26)-WRK showed more potent activity against drug-resistant bacteria. It was also resistant to physiological salts and human serum and acted synergistically in combination with conventional antibiotics, such as chloramphenicol, ciprofloxacin, and oxacillin, suggesting that combined with conventional antibiotics, it is a promising adjuvant. Furthermore, membrane depolarization, SYTOX Green uptake, and flow cytometry revealed that it kills bacteria by damaging their membrane integrity. Therefore, this study suggests that Fowl-1 (8-26)-WRK has considerable potential for future development as an antimicrobial and anti-inflammatory agent for treating antibiotic-resistant infections.
鸡肠抗菌肽 Fowlicidin-1（Fowl-1）具有抗菌和抗炎特性。然而，由于其对宿主细胞的高细胞毒性，其药物开发最终受到了影响。在本研究中，合成了一系列 N-和 C-端截断的 19 肽 Fowl-1 肽。在这些截断的肽中，Fowl-1（8-26）表现出广谱抗菌活性，而对人红细胞无细胞毒性，同时降低了抗炎活性。进一步，通过 Thr→Trp、Ile→Arg 和 Asn→Lys 取代 Fowl-1（8-26）设计了 Fowl-1（8-26）-WRK，使其具有更多的两亲性。结果表明，它同时具有抗菌和抗炎特性。本研究还表明，Fowl-1（8-26）-WRK 对 LPS 诱导的炎症的抑制活性主要归因于 LPS 与肽的结合。有趣的是，与人类抗菌肽 LL-37 和蜂毒素相比，Fowl-1（8-26）-WRK 对耐药菌表现出更强的活性。它还能抵抗生理盐水和人血清，并与常规抗生素（如氯霉素、环丙沙星和苯唑西林）协同作用，这表明与常规抗生素联合使用时，它是一种有前途的佐剂。此外，膜去极化、SYTOX Green 摄取和流式细胞术表明，它通过破坏细菌的膜完整性来杀死细菌。因此，本研究表明，Fowl-1（8-26）-WRK 具有作为治疗抗药性感染的抗菌和抗炎药物的巨大潜力。
