细菌分选酶A抑制剂抗革兰阳性超级细菌感染的作用及其应用前景

Anti-superbacterial infection of bacterial sortase A inhibitors and their prospects of application

过去几十年中,全球抗菌药物耐药形势愈发严峻,多重耐药菌所致感染性疾病的发病率及死亡率逐年上升。对抗菌药物耐药机制的研究发现,抗毒力疗法可能成为对抗超级细菌感染的新选择。细菌分选酶A(SrtA)是一种细菌细胞膜酶,可将关键毒力因子固定在革兰阳性菌细胞壁表面,在革兰阳性超级细菌的致病机制中起重要作用。SrtA通过识别、硫酯化和转肽化将微生物表面成分识别黏附基质分子锚定在细菌肽聚糖上,因此抑制SrtA可使细菌无法附着在特定的组织和(或)器官上,从而无法攻击宿主细胞,且无法逃避宿主的免疫反应。此外,SrtA并非细菌生长和生存所必需,在细胞膜上很容易获得,是开发抗毒力疗法药物的理想靶点。本文对合成小分子、多肽和天然产物等SrtA抑制剂的研究进展进行归纳,同时对SrtA抑制剂治疗革兰阳性超级细菌感染的应用潜力进行了分析。

Over the past decades,global antimicrobial resistance has become increasingly prevalent,and the morbidity and mortality of infectious diseases caused by multidrug-resistant bacteria have increased year by year.The research on antimicrobial resistance mechanisms has found that the antivirulence therapy may be a new option for fighting superbug infections.Bacterial sortase A(SrtA),a bacterial cell embrane enzyme that immobilizes key virulence factors on the cell wall surface of ram-positive bacteria,plays an important role in the pathogenesis of Gram-positive superbugs.Through recognition,thioesterification and transpeptidation of microbial surface components,SrtA anchors adhesion matrix molecules to bacterial peptidoglycan,thus preventing bacteria from clinging to specific tissues/organs by inhibiting SrtA and making it impossible for them to attack host cells or evade the host's immune response.Furthermore,SrtA is not required for bacterial growth or activity and is readily available on the cell membrane,making it an ideal target for the development of antivirulence therapy drugs.In this paper,the research progress in synthetic small molecules,peptides,natural products and other SrtA inhibitors is summarized,and the applicability of SrtA inhibitors in the treatment of super bacterial infections is analyzed.