PEP27, a 27-amino acid (aa) peptide secreted by Streptococcus pneumoniae, is an autolytic peptide that functions as a major virulence factor. To develop a clinically applicable antimicrobial peptide (AMP), we designed PEP27 analogs with Trp substitutions to enhance its antimicrobial activity compared to that of PEP27. Particularly, PEP27-2 showed strong antimicrobial activity against a wide variety of bacteria, including multidrug-resistant (MDR) bacteria. It was found that the antimicrobial activity of PEP27-2 was increased by substituting Trp for the aa at the middle position of PEP27. We found that PEP27-2 acts as an effective cell-penetrating peptide in bacterial and mammalian cells. Here, we proved that subcutaneous infection with MDR Staphylococcus aureus induced skin lesions such as skeletal muscle damage, deep inflammation, and necrosis of the overlaying dermis in mice. Combination treatment with antibiotics revealed synergistic effects, remarkably reducing abscess size and improving the bacteria removal rate from the infection site. Moreover, PEP27-2–antibiotic combination treatment reduced inflammation, lowering levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, inducible NO synthase (iNOS), and cyclooxygenase (COX-2) in skin abscess tissue. The results suggest that the PEP27-2 peptide is a promising therapeutic option for combating MDR bacterial strains by enhancing antibiotic penetration and protecting against MDR bacteria.

中文翻译：

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PEP27-2 是一种有效的抗微生物细胞穿透肽，与抗生素联合使用时，可减少小鼠金黄色葡萄球菌感染期间皮肤脓肿的形成

PEP27是一种由肺炎链球菌分泌的 27 个氨基酸 (aa) 肽，是一种自溶肽，可作为主要毒力因子。为了开发临床适用的抗菌肽 (AMP)，我们设计了具有 Trp 取代的 PEP27 类似物，以增强其与 PEP27 相比的抗菌活性。特别是，PEP27-2 对多种细菌表现出很强的抗菌活性，包括耐多药 (MDR) 细菌。发现 PEP27-2 的抗菌活性通过用 Trp 取代 PEP27 中间位置的 aa 增加。我们发现 PEP27-2 在细菌和哺乳动物细胞中充当有效的细胞穿透肽。在这里，我们证明了 MDR金黄色葡萄球菌的皮下感染诱导皮肤损伤，如骨骼肌损伤、深层炎症和小鼠覆盖真皮坏死。与抗生素联合治疗显示出协同作用，显着减少脓肿大小并提高感染部位的细菌去除率。此外，PEP27-2-抗生素联合治疗减少炎症，降低肿瘤坏死因子-α (TNF-α)、白介素-1β (IL-1β)、IL-6、诱导型 NO 合酶 (iNOS) 和环氧合酶 (COX) 的水平-2) 在皮肤脓肿组织中。结果表明，PEP27-2 肽是一种有前景的治疗选择，可通过增强抗生素渗透和防止 MDR 细菌来对抗 MDR 细菌菌株。