Identification of anti-Mycobacterium tuberculosis agents targeting the interaction of bacterial division proteins FtsZ and SepFe  

作　　者：Hongjuan Zhang Ying Chen Yu Zhang Luyao Qiao Xiangyin Chi Yanxing Han Yuan Lin Shuyi Si Jiandong Jiang 

机构地区：[1]State Key Laboratory of Bioactive Substance and Function of Natural Medicines,Institute of Materia Medica,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100050,China [2]Institute of Medicinal Biotechnology,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100050,China

出　　处：《Acta Pharmaceutica Sinica B》2023年第5期2056-2070,共15页药学学报（英文版）

基　　金：CAMS Innovation Fund for Medical Sciences(CIFMS)(2021-I2M-1-026,2022-I2M-2-002,2021I2M-JB-011,China);National Natural Science Foundation of China(No.81773784);Beijing Key Laboratory of NonClinical Drug Metabolism and PK/PD study(Z141102004414062,China)。

摘　　要：Tuberculosis(TB)is one of the deadly diseases caused by Mycobacterium tuberculosis(Mtb),which presents a significant public health challenge.Treatment of TB relies on the combination of several anti-TB drugs to create shorter and safer regimens.Therefore,new anti-TB agents working by different mechanisms are urgently needed.FtsZ,a tubulin-like protein with GTPase activity,forms a dynamic Z-ring in cell division.Most of FtsZ inhibitors are designed to inhibit GTPase activity.In Mtb,the function of Z-ring is modulated by SepF,a FtsZ binding protein.The FtsZ/SepF interaction is essential for FtsZ bundling and localization at the site of division.Here,we established a yeast twohybrid based screening system to identify inhibitors of FtsZ/SepF interaction in M.tuberculosis.Using this system,we found compound T0349 showing strong anti-Mtb activity but with low toxicity to other bacteria strains and mice.Moreover,we have demonstrated that T0349 binds specifically to SepF to block FtsZ/SepF interaction by GST pull-down,fluorescence polarization(FP),surface plasmon resonance(SPR)and CRISPRi knockdown assays.Furthermore,T0349 can inhibit bacterial cell division by inducing filamentation and abnormal septum.Our data demonstrated that FtsZ/SepF interaction is a promising anti-TB drug target for identifying agents with novel mechanisms.

关 键 词：Anti-Mycobacterium tuberculosis FTSZ SepF Bacterial division Yeast two-hybrid CRISPRi Protein—protein interaction Inhibitor 

分 类 号：R978.3[医药卫生—药品]