Moreno-Morales Javier, Martín-Vilardell Núria, Guardiola Salvador, Vila-Farrés Xavier, Cebrero Tania, Babić Marko, Ballesté-Delpierre Clara, Kalafatović Daniela, Giralt Ernest, Pachón-Ibañez María Eugenia, Vila Jordi
Barcelona Institute for Global Health (ISGlobal), 08036 Barcelona, Spain.
Department of Basic Clinical Practice, Faculty of Medicine and Health Sciences, University of Barcelona, 08036 Barcelona, Spain.
Antibiotics (Basel). 2025 Aug 19;14(8):838. doi: 10.3390/antibiotics14080838.
: Infections caused by multidrug-resistant (MDR) are steadily increasing, thus the discovery and development of new and effective agents are needed. Antimicrobial peptides (AMPs) are a heterogeneous group of innate defense system peptides with broad antimicrobial activity. In this study, 17 AMPs were tested, identifying CAP-18, a cathelicidin-based compound, as the most active. CAP-18 was optimized by synthesizing structural derivatives, which were selected for further studies based on their activity against a collection of MDR and colistin-resistant strains. : AMPs collection was initially tested against different strains, identifying CAP-18 as the most active. CAP-18 derivatives were synthetized and assessed by the Minimum Inhibitory Concentration (MIC), time-kill kinetics, cytotoxicity against human cell lines, hemolytic activity, and therapeutic index (IC/MIC). The mechanism of action was assessed by Transmission Electron Microscopy (TEM), and in vivo efficacy was determined through a murine skin infection model. : CAP-18 and D-CAP-18 had a MIC of 4 and 2 μg/mL, respectively, whereas CAP-18 and D-CAP-18 presented MIC values of 16 mg/L. The shorter derivatives of CAP-18 showed a lower activity. Time-kill curves revealed a fast bactericidal effect. These derivatives showed low toxicity against different human cell lines and low hemolysis, resulting in a wide therapeutic index (IC/MIC), with D-CAP-18 having the best therapeutic index (137.4). TEM provided insight into the mechanism of action, revealing bacterial membrane damage. In vivo studies of both CAP-18 and D-CAP-18 showed good activity with a 3 log decrease compared to the infected control group. : Among the investigated four peptides, D-CAP-18 is the most promising candidate to treat skin infections caused by MDR since it shows potent activity both in vitro and in vivo, and a high therapeutic index.
多重耐药菌（MDR）引起的感染正在稳步增加，因此需要发现和开发新的有效药物。抗菌肽（AMPs）是一类具有广泛抗菌活性的先天性防御系统肽的异质群体。在本研究中，测试了17种抗菌肽，确定基于cathelicidin的化合物CAP-18是活性最强的。通过合成结构衍生物对CAP-18进行优化，根据它们对一系列多重耐药菌和耐黏菌素菌株的活性选择进一步研究的对象。：最初针对不同菌株测试抗菌肽集合，确定CAP-18是活性最强的。合成CAP-18衍生物，并通过最低抑菌浓度（MIC）、时间杀菌动力学、对人细胞系的细胞毒性、溶血活性和治疗指数（IC/MIC）进行评估。通过透射电子显微镜（TEM）评估作用机制，并通过小鼠皮肤感染模型确定体内疗效。：CAP-18和D-CAP-18的MIC分别为4和2μg/mL，而CAP-18和D-CAP-18的MIC值为16mg/L。CAP-18的较短衍生物活性较低。时间杀菌曲线显示出快速杀菌作用。这些衍生物对不同人细胞系显示出低毒性和低溶血作用，导致治疗指数（IC/MIC）较宽，其中D-CAP-18的治疗指数最佳（137.4）。TEM深入了解了作用机制，揭示了细菌膜损伤。CAP-18和D-CAP-18的体内研究均显示出良好的活性，与感染对照组相比细菌数量减少了3个对数级。：在所研究的四种肽中，D-CAP-18是治疗多重耐药菌引起的皮肤感染最有前景的候选药物，因为它在体外和体内均显示出强效活性以及高治疗指数。
