State Key Laboratory for Zoonotic Diseases, Key Laboratory for Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China.
The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China.
Fitoterapia. 2022 Oct;162:105261. doi: 10.1016/j.fitote.2022.105261. Epub 2022 Aug 6.
Streptococcus pneumoniae (S. pneumoniae) is a major Gram-positive opportunistic pathogen that causes pneumonia, bacteremia, and other fatal infections. This bacterium is responsible for more deaths than any other single pathogen in the world. Inexplicably, these symptoms persist despite the administration of effective antibiotics. Targeting pneumolysin (PLY) and sortase A (SrtA), the major virulence factors of S. pneumoniae, this study uncovered a novel resistance mechanism to S. pneumoniae infection. Using protein phenotype assays, we determined that the small molecule inhibitor alnustone is a potent drug that inhibits both PLY and SrtA. As essential virulence factors of S. pneumoniae, PLY and SrtA play a significant role in the occurrence of infection. Furthermore, evaluation using PLY-mediated hemolysis assay demonstrated alunstone had the potential to interrupt the haemolytic activity of PLY with treatment alunstone (4 μg/ml). Co-incubation of S. pneumoniae D39 SrtA with small-molecule inhibitors decreases cell wall-bound Nan A (pneumococcal-anchored surface protein SrtA), inhibits biofilm formation, and reduces biomass significantly. The protective effect of invasive pneumococcal disease (IPD) on murine S. pneumoniae was demonstrated further. Our study proposes a comprehensive bacteriostatic mechanism for S. pneumoniae and highlights the significant translational potential of targeting both PLY and SrtA to prevent pneumococcal infections. Our findings indicate that the antibacterial strategy of directly targeting PLY and SrtA with alnustone is a promising treatment option for S. pneumoniae and that alnustone is a potent inhibitor of PLY and SrtA.
肺炎链球菌（Streptococcus pneumoniae，S. pneumoniae）是一种主要的革兰氏阳性机会致病菌，可导致肺炎、菌血症和其他致命感染。这种细菌是导致世界上任何单一病原体死亡人数最多的细菌。令人费解的是，尽管使用了有效的抗生素，这些症状仍持续存在。本研究针对肺炎链球菌的主要毒力因子肺炎球菌溶血素（Pneumolysin，PLY）和天冬酰胺基内肽酶 A（Sortase A，SrtA），发现了一种针对肺炎链球菌感染的新的耐药机制。通过蛋白表型分析，我们确定小分子抑制剂阿努司他是一种强效药物，可同时抑制 PLY 和 SrtA。作为肺炎链球菌的重要毒力因子，PLY 和 SrtA 在感染的发生中起着重要作用。此外，使用 PLY 介导的溶血试验评估表明，阿努司他具有潜在的中断 PLY 溶血活性的作用，且随着阿努司他（4μg/ml）的处理，溶血活性降低。肺炎链球菌 D39 SrtA 与小分子抑制剂共孵育可降低细胞壁结合的 Nan A（肺炎球菌锚定表面蛋白 SrtA），抑制生物膜形成，并显著减少生物量。进一步证明了侵袭性肺炎球菌病（Invasive Pneumococcal Disease，IPD）对小鼠肺炎链球菌的保护作用。我们的研究提出了一种针对肺炎链球菌的全面抑菌机制，并强调了靶向 PLY 和 SrtA 以预防肺炎链球菌感染的重要转化潜力。我们的研究结果表明，直接针对 PLY 和 SrtA 的阿努司他的抗菌策略是治疗肺炎链球菌的一种很有前途的治疗方法，并且阿努司他是 PLY 和 SrtA 的有效抑制剂。
