The Laboratory of Molecular Nutrition and Immunity, Institute of Animal Nutrition, Northeast Agricultural University, Harbin 150030 P. R. China.
J Med Chem. 2022 Apr 14;65(7):5355-5373. doi: 10.1021/acs.jmedchem.1c01485. Epub 2022 Mar 16.
The unusual acidic pH of the abscess milieu is an adverse factor that decreases the therapeutic efficacy of traditional antibiotics. Moreover, avoiding both the undesired killing of commensal bacteria and the development of drug resistance remains difficult during abscess therapy. Hence, we synthesized a series of pH-responsive antimicrobial peptides equipped with efficient bacterial killing activity at pH 6.5 and inactivity at pH 7.4. Among the peptides, F5 exhibited outstanding pH-responsive antimicrobial activity and low toxicity. Fluorescence spectroscopy and electron microscopy illustrated that F5 killed bacteria via a membrane-disruptive mechanism at acidic pH values. Mouse cutaneous abscesses revealed that F5 was equipped with excellent therapeutic ability to reduce the bacterial load and cytokines without causing skin toxicity. In summary, this study reveals a strategy for selectively killing bacteria under the pathologic conditions of abscess sites while avoiding the elimination of commensal bacteria under normal physiological pH levels.
脓肿环境中异常的酸性 pH 值是一个不利因素，它降低了传统抗生素的治疗效果。此外，在脓肿治疗过程中，既要避免不必要地杀死共生菌，又要避免产生耐药性，这仍然很困难。因此，我们合成了一系列 pH 响应型抗菌肽，它们在 pH 6.5 时具有高效的杀菌活性，而在 pH 7.4 时没有活性。在这些肽中，F5 表现出优异的 pH 响应抗菌活性和低毒性。荧光光谱和电子显微镜表明，F5 通过在酸性 pH 值下破坏细胞膜的机制杀死细菌。小鼠皮肤脓肿表明，F5 具有出色的治疗能力，可降低细菌负荷和细胞因子，而不会引起皮肤毒性。总之，这项研究揭示了一种在脓肿部位病理条件下选择性杀死细菌的策略，同时避免在正常生理 pH 值下消除共生菌。
