牛乳腺炎是泌乳牛的常见感染,造成巨大的经济损失。金黄色葡萄球菌是主要的病原体,这导致反复和持续的乳房内感染,因为常规抗生素对它无效。Mastoparan样肽是具有广泛抗菌潜力的多功能分子,构成一个有吸引力的选择。然而,它们对宿主细胞的毒性阻碍了它们的治疗应用。以前,我们的小组设计了三种乳齿旁兰-L类似物,即mastoparan-MO,mastoparan-R1和[I5,R8]MP,以提高细胞选择性和潜能。这里,我们感兴趣的是比较乳油-L及其类似物对金黄色葡萄球菌菌株的牛乳腺炎分离株的抗菌功效,与序列修饰促进的物理化学性质和结构排列变化相关。因此,类似物的溶血和/或抗菌活性平衡。所有的肽在疏水和膜模拟环境中都显示出α-螺旋折叠,由圆二色性确定。肽[I5,R8]MP因其增强的选择性和与mastoparan-L和其他衍生物相关的抗菌特性而脱颖而出。生物物理方法显示,[I5,R8]MP快速去极化金黄色葡萄球菌的细菌膜,通过随后的膜破坏导致细胞死亡。我们的结果表明,[I5,R8]MP肽可能是开发用于治疗牛乳腺炎的基于肽的药物的起点,牛奶中没有残留物的优点,这将有助于减少经典抗生素的使用。重要金黄色葡萄球菌是乳腺炎的主要原因,世界上最重要的奶牛疾病。金黄色葡萄球菌的多药耐药性和人畜共患潜力,除了牛奶中抗生素残留的可能性,对公众和动物健康至关重要。抗菌肽提供了一种新的抗菌策略。这里,我们证明[I5,R8]MP是一种有效的选择性肽,通过靶向细菌膜作用于金黄色葡萄球菌。因此,了解这类抗菌剂的物理化学决定因素和作用方式为在牛乳腺炎背景下具有增强活性的肽开发开辟了新的前景。
Bovine mastitis is a frequent infection in lactating cattle, causing great economic losses. Staphylococcus aureus represents the main etiological agent, which causes recurrent and persistent intramammary infections because conventional antibiotics are ineffective against it. Mastoparan-like peptides are multifunctional molecules with broad antimicrobial potential, constituting an attractive alternative. Nevertheless, their toxicity to host cells has hindered their therapeutic application. Previously, our group engineered three mastoparan-L analogs, namely mastoparan-MO, mastoparan-R1, and [I5, R8] MP, to improve cell selectivity and potential. Here, we were interested in comparing the antibacterial efficacy of mastoparan-L and its analogs against bovine mastitis isolates of S. aureus strains, making a correlation with the physicochemical properties and structural arrangement changes promoted by the sequence modifications. As a result, the analog\'s hemolytic and/or antimicrobial activity was balanced. All the peptides displayed α-helical folding in hydrophobic and membrane-mimetic environments, as determined by circular dichroism. The peptide [I5, R8] MP stood out for its enhanced selectivity and antibacterial features related to mastoparan-L and the other derivatives. Biophysical approaches revealed that [I5, R8] MP rapidly depolarizes the bacterial membrane of S. aureus, causing cell death by subsequent membrane disruption. Our results demonstrated that the [I5, R8] MP peptide could be a starting point for the development of peptide-based drugs for the treatment of bovine mastitis, with the advantage of no residue in milk, which would help reduce the use of classical antibiotics.IMPORTANCEStaphylococcus aureus is a leading cause of mastitis, the world\'s most important dairy cattle disease. The multidrug resistance and zoonotic potential of S. aureus, besides the likelihood of antibiotic residues in milk, are of critical concern to public and animal health. Antimicrobial peptides offer a novel antimicrobial strategy. Here, we demonstrate that [I5, R8] MP is a potent and selective peptide, which acts on S. aureus by targeting the bacterial membrane. Therefore, understanding the physicochemical determinants and the modes of action of this class of antimicrobials opens novel prospects for peptide development with enhanced activities in the bovine mastitis context.