匹维溴铵增效贝达喹啉抗结核活性的发现及作用机制研究

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中图分类号：R978.3 文献标志码：A

Discovery of pinaverium bromide as a potentiator of bedaquiline against tuberculosis and its mechanism of action

LiangWenwen，ZhangYe，QiXianglong，LuYu，andXuJian （Beijing Chest HospitalAfliated toCapitalMedicalUniversityBeijingTuberculosis ChestCancer Institute，Beijing101149）

Abstract Objective To screen the potentiator of the anti-tuberculosis drug bedaquiline （BDQ）and investigate the synergistic anti-tuberculosis activity and potential mechanism of action of pinaverium bromide in combination with BDQ. MethodsAn in vitro model using the Mycobacterium tuberculosis Rv0678 mutant was established to screen for BDQ potentiators. An MmpS5 knockout strain （△S5） with disrupted MmpL5-MmpS5 function was constructed.The activityof pinaverium bromide in combination with BDQ was evaluated in M. tuberculosis strains with different expression levels of MmpL5-MmpS5.The checkerboard assy was used to assess the combined activity of pinaverium bromide with various anti-tuberculosis drugs.The anti-tuberculosis activity of pinaverium bromide in combination with BDQ was further evaluated using an in vitro time-killkinetic assay.ResultsPinaverium bromide at 1/12× MIC （0.5μg/mL ）reduced theMICofBDQagainst the RνO678 mutant by 32-fold，which was even lower than the MIC of BDQ against M. tuberculosis H37Rv （0.06μg/mL ）.No synergistic activity Was observed in the knockout strain△S5 with disrupted MmpL5-MmpS5 function.Pinaverium bromide showed synergistic activity when combined with BDQ，clofazimine，and PBTZ169，which are substrates of the MmpL5-MmpS5 eflux system， but did not show synergy with other anti-tuberculosis drugs.Time-killcurves showed that the combination of pinaverium bromide and BDQhad synergistic bactericidal activity.ConclusionPinaverium bromide potentiates significantly the antituberculosis activityofBDQthrough the inhibition ofthe MmpL5-MmpS5complex.The discovery of his potentiator provides a new potential strategy for the development of novel anti-drug-resistant tuberculosis agents.

Key WordsMycobacterium tuberculosis; Pinaverium bromide; Bedaquiline; MmpL5-MmpS5; Synergy

结核病（tuberculosis，TB）是一种严重危害人类健康的慢性传染性疾病，已成为全球重大公共卫生问题。（剩余13584字）