School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan 430074, P. R. China.
Key Laboratory of Catalysis and Energy Materials Chemistry of Ministry of Education & Hubei Key Laboratory of Catalysis and Materials Science, South Central University for Nationalities, Wuhan 430074, China.
ACS Appl Mater Interfaces. 2022 Jan 12;14(1):159-171. doi: 10.1021/acsami.1c17271. Epub 2021 Dec 20.
An "antibiotic-free strategy" provides a viable option to address bacterial infections, especially for the "superbug" challenge. However, the undesirable antibacterial activity of antibiotic-free agents hinders their practical applications. In this study, we developed a combination antibacterial strategy of coupling peptide-drug therapy with chemodynamic therapy (CDT) to achieve the effective bacterial inhibition. An amphiphilic oligopeptide (LAOOH-OPA) containing a therapeutic unit of (KLAK) peptide and a hydrophobic linoleic acid hydroperoxide (LAHP) was designed. The positively charged (KLAK) peptide with an α-helical conformation enabled rapid binding with microbial cells via electrostatic interaction and subsequent membrane insertion to deactivate the bacterial membrane. When triggered by Fe, moreover, LAHP could generate singlet oxygen (O) to elicit lipid bilayer leakage for enhanced bacteria inhibition. In vitro assays demonstrated that the combination strategy possessed excellent antimicrobial activity not only merely toward susceptible strains (Gram-positive and Gram-negative ) but also toward methicillin-resistant (MRSA). On the mouse skin abscess model induced by , self-assembled LAOOH-OPA exhibited a more significant bacteria reduction (1.4 log reduction) in the bioburden compared to that of the standard vancomycin (0.9 log reduction) without apparent systemic side effects. This combination antibacterial strategy shows great potential for effective bacterial inhibition.
一种“无抗生素策略”为解决细菌感染提供了一种可行的选择，特别是对于“超级细菌”的挑战。然而，无抗生素试剂的不良抗菌活性阻碍了它们的实际应用。在本研究中，我们开发了一种将肽药物治疗与化学动力学治疗（CDT）相结合的联合抗菌策略，以实现有效的细菌抑制。设计了一种含有治疗单位（KLAK）肽和疏水性亚油酸氢过氧化物（LAHP）的两亲性寡肽（LAOOH-OPA）。带正电荷的（KLAK）肽具有α-螺旋构象，通过静电相互作用和随后的膜插入与微生物细胞快速结合，从而使细菌膜失活。此外，当被 Fe 触发时，LAHP 可以产生单线态氧（O）以引发脂质双层泄漏，从而增强对细菌的抑制作用。体外实验表明，该联合策略不仅对敏感菌株（革兰氏阳性菌和革兰氏阴性菌）具有优异的抗菌活性，而且对耐甲氧西林金黄色葡萄球菌（MRSA）也具有优异的抗菌活性。在由金黄色葡萄球菌诱导的小鼠皮肤脓肿模型中，与标准万古霉素（0.9 对数减少）相比，自组装的 LAOOH-OPA 在生物负荷中表现出更高的细菌减少（1.4 对数减少），而没有明显的全身副作用。这种联合抗菌策略显示出有效抑制细菌的巨大潜力。
