Ye Xinyue, Huang Ya, Zhou Chenyu, Liu Xiaoyun, Zhao Wenxuan, Zhao Xiurong, Xie Xiaolin, Wang Liping, Bai Zhaoshi, Zhou Changlin, Ma Lingman
School of Life Science and Technology, China Pharmaceutical University, 639 Longmian Road, Nanjing, Jiangsu, 211198, China.
Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & the Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210009, China.
Microbiol Res. 2021 Oct 27;255:126909. doi: 10.1016/j.micres.2021.126909.
Development of novel therapeutic strategies and antibacterial agents against antibiotic-resistant Staphylococcus aureus (S. aureus) is urgent. In this study, antibacterial activities and possible mechanisms of peptide MSI-1 against multiple drug-resistant S. aureus were investigated. Results demonstrated that MSI-1 had potent bacteriostatic activity and bactericidal efficiency against S. aureus, including methicillin-resistant S. aureus (MRSA), vancomycin-intermediate S. aureus (VISA) and vancomycin-resistant S. aureus (VRSA), with minimum inhibitory concentrations (MICs) ranging from 4 to 16 μg/mL and bactericidal times from 2-12 h. MSI-1 exhibited a low incidence of developing resistance and additive effects with vancomycin to overcome MRSA and VRSA. Moreover, MSI-1, even at sub-MIC concentrations, inhibited staphyloxanthin (STX) production of S. aureus. This inhibitory effect was unique and effectively sensitized S. aureus to host immune defense. In terms of its modes of action, MSI-1 disrupted the cell membrane of S. aureus by binding to negatively-charged lipoteichoic acid to exert a direct bactericidal effect. Interestingly, MSI-1 interacted with 4,4'-diapophytoene desaturase (CrtN) of S. aureus via ionic bonds, hydrogen bonds, and Pi-Pi or Pi-alkyl interactions, and alanine substitution of the key amino acids contributed to these interactions weakened this STX production inhibition. Thus, in a MRSA-induced skin infection in mice and MRSA/VRSA-induced systemic infection in Galleria mellonella,MSI-1 alleviated staphylococcal scalded skin syndrome to promote mouse skin wound repair and mitigated staphylococcus infection-induced immune melanization to enhance G. mellonella survival. Collectively, MSI-1 has potent antibacterial activity against drug-resistant S. aureus by affecting bacterial viability and exerting its anti-virulence effects. It can be developed as a new antibacterial agent to resist refractory S. aureus infection.
开发针对耐抗生素金黄色葡萄球菌（S. aureus）的新型治疗策略和抗菌剂迫在眉睫。在本研究中，研究了肽MSI-1对多重耐药金黄色葡萄球菌的抗菌活性及可能机制。结果表明，MSI-1对金黄色葡萄球菌具有强大的抑菌活性和杀菌效率，包括耐甲氧西林金黄色葡萄球菌（MRSA）、万古霉素中介金黄色葡萄球菌（VISA）和耐万古霉素金黄色葡萄球菌（VRSA），其最低抑菌浓度（MIC）范围为4至16μg/mL，杀菌时间为2至12小时。MSI-1产生耐药性的发生率较低，且与万古霉素具有协同作用以克服MRSA和VRSA。此外，即使在亚MIC浓度下，MSI-1也能抑制金黄色葡萄球菌的 staphyloxanthin（STX）产生。这种抑制作用独特且有效地使金黄色葡萄球菌对宿主免疫防御敏感。就其作用方式而言，MSI-1通过与带负电荷的脂磷壁酸结合破坏金黄色葡萄球菌的细胞膜，从而发挥直接杀菌作用。有趣的是，MSI-1通过离子键、氢键和π-π或π-烷基相互作用与金黄色葡萄球菌的4,4'-二脱辅基八氢番茄红素去饱和酶（CrtN）相互作用，关键氨基酸的丙氨酸取代导致这些相互作用减弱，从而削弱了对STX产生的抑制作用。因此，在小鼠的MRSA诱导的皮肤感染和大蜡螟的MRSA / VRSA诱导的全身感染中，MSI-1减轻了葡萄球菌烫伤样皮肤综合征，促进了小鼠皮肤伤口修复，并减轻了葡萄球菌感染诱导的免疫黑化，以提高大蜡螟的存活率。总体而言，MSI-1通过影响细菌活力并发挥其抗毒力作用，对耐药金黄色葡萄球菌具有强大的抗菌活性。它可以开发成为一种新型抗菌剂，以抵抗难治性金黄色葡萄球菌感染。
