State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, 2 Sipailou, Nanjing, 210096, P. R. China.
Adv Healthc Mater. 2023 Jul;12(18):e2203283. doi: 10.1002/adhm.202203283. Epub 2023 Mar 16.
Staphylococcus aureus (S. aureus) remains a leading cause of bacterial infections. However, eradication of S. aureus infections with common antibiotics is increasingly difficult due to outbreaks of drug resistance. Therefore, new antibiotic classes and antibacterial strategies are urgently in demand. Herein, it is shown that an adamantane-peptide conjugate, upon dephosphorylation by alkaline phosphatase (ALP) constitutively expressed on S. aureus, generates fibrous assemblies in situ to combat S. aureus infection. By attaching adamantane to a phosphorylated tetrapeptide Nap-Phe-Phe-Lys-Tyr(H PO )-OH, the rationally designed adamantane-peptide conjugate Nap-Phe-Phe-Lys(Ada)-Tyr(H PO )-OH (Nap-FYp-Ada) is obtained. Upon bacterial ALP activation, Nap-FYp-Ada is dephosphorylated and self-assembles into nanofibers on the surface of S. aureus. As revealed by cell assays, the assemblies of adamantane-peptide conjugates interact with cell lipid membrane and thereby disrupt membrane integrity to kill S. aureus. Animal experiments further demonstrate the excellent potential of Nap-FYp-Ada in the treatment of S. aureus infection in vivo. This work provides an alternative approach to design antimicrobial agents.
金黄色葡萄球菌（S. aureus）仍然是细菌性感染的主要原因。然而，由于耐药性的爆发，用常见抗生素根除金黄色葡萄球菌感染变得越来越困难。因此，急需新的抗生素类别和抗菌策略。本文表明，在金黄色葡萄球菌上持续表达的碱性磷酸酶（ALP）将金刚烷-肽缀合物去磷酸化后，会原位生成纤维组装体以抵抗金黄色葡萄球菌感染。通过将金刚烷附着到磷酸化的四肽 Nap-Phe-Phe-Lys-Tyr（H PO ）-OH 上，设计合理的金刚烷-肽缀合物 Nap-Phe-Phe-Lys（Ada）-Tyr（H PO ）-OH（Nap-FYp-Ada）。在细菌 ALP 激活后，Nap-FYp-Ada 被去磷酸化并在金黄色葡萄球菌表面自组装成纳米纤维。细胞实验表明，金刚烷-肽缀合物的组装与细胞膜相互作用，从而破坏膜的完整性以杀死金黄色葡萄球菌。动物实验进一步证明了 Nap-FYp-Ada 在体内治疗金黄色葡萄球菌感染方面的巨大潜力。这项工作为设计抗菌剂提供了一种替代方法。
