Antimicrobial peptides (AMPs) are a potential alternative to classical antibiotics that are yet to achieve a therapeutic breakthrough for treatment of systemic infections. The antibacterial potency of pleurocidin, an AMP from Winter Flounder, is linked to its ability to cross bacterial plasma membranes and seek intracellular targets while also causing membrane damage. Here we describe modification strategies that generate pleurocidin analogues with substantially improved, broad spectrum, antibacterial properties, which are effective in murine models of bacterial lung infection. Increasing peptide–lipid intermolecular hydrogen bonding capabilities enhances conformational flexibility, associated with membrane translocation, but also membrane damage and potency, most notably against Gram-positive bacteria. This negates their ability to metabolically adapt to the AMP threat. An analogue comprising d-amino acids was well tolerated at an intravenous dose of 15 mg/kg and similarly effective as vancomycin in reducing EMRSA-15 lung CFU. This highlights the therapeutic potential of systemically delivered, bactericidal AMPs.

抗菌肽（AMP）是经典抗生素的潜在替代品，但在治疗全身感染方面尚未取得突破。杀菌素（一种来自冬鲽鱼的 AMP）的抗菌效力与其穿过细菌质膜并寻找细胞内靶标同时造成膜损伤的能力有关。在这里，我们描述了产生具有显着改善的广谱抗菌特性的截短截短草素类似物的修饰策略，其在细菌性肺部感染的小鼠模型中有效。增加肽-脂质分子间氢键能力可增强与膜易位相关的构象灵活性，但也可增强膜损伤和效力，尤其是针对革兰氏阳性菌。这否定了它们代谢适应 AMP 威胁的能力。包含d-氨基酸的类似物在15mg/kg的静脉内剂量下具有良好的耐受性，并且在降低EMRSA-15肺CFU方面与万古霉素类似地有效。这凸显了全身递送的杀菌 AMP 的治疗潜力。