The Discovery of a Drug Candidate as an Enhancer of Glutamate Kinase to Kill Mycobacterium Tuberculosis

A recent paper entitled “Quinoline derivatives kill Mycobacterium tuberculosis by activating glutamate kinase”, published in Cell Chemical Biology on 14 of June, 2019, demonstrates that mycobacterial glutamate kinase may be a potential target for novel anti-tuberculosis (TB) drugs. The work was performed with the collaboration of Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences (GIBH, CAS), Guangzhou Regenerative Medicine and Health, Guangdong Laboratory (GRMH-GDL), Guangzhou Chest Hospital, Shenzhen Third People's Hospital, and KTH Royal Institute of Technology, AlbaNova University Center. Gaelle G. Makafe and Muzammal Hussain, both PhD students from State Key Laboratory of Respiratory Disease and GRMH-GDL, are co-first authors of the paper. Professor Jinsong Liu and professor Tianyu Zhang are co-corresponding authors. This study was greatly boosted by assistance offered by research teams of Jiancun Zhang and Qiang Zhu. 
   

TB, primarily caused by Mycobacterium tuberculosis (Mtb), represents one of the most important deadly diseases. The disease once became less dangerous thanks to the introduction of anti-TB drugs. However, as with mounting cases of drug-resistant TB, coinfection with human immunodeficiency virus (HIV), and infection in immunocompromised patients, resurgence of TB has occurred. Indeed, according to World Health Organization (WHO) Global Tuberculosis Report, over 10 million new TB cases and 1.6 million TB-related mortalities have been reported annually since 2016, making TB the largest and most important infectious disease worldwide. The lack of novel anti-TB fist-line drugs over the past 50 years asks urgently for the development of effective drug candidates with new modes of action and without significant adverse effects.
   

Currently, target-based screening of anti-TB agents mainly focuses on the identification of putative inhibitors. In the study, Makafe and colleagues found that new quinoline compounds, i.e. Z0933/Z0930 (authorized patent: ZL201310385431.X), works as a prodrug and the active form competes with proline to bind glutamate kinase which catalyzes the first step of proline synthesis, leading to an enhanced glutamate kinase activity and thus compromising proline-mediated negative feedback mechanism. Treatment with these compounds increased mycobacterial proline level intracellularly, possibly leading to an augmented ATP and reactive oxygen species (ROS) production in the electron transport chain. The augmented ROS production was proposed to account for the quinoline compound-induced cell death. This study also showed that A226S mutation in glutamate kinase compromised the effect of Z0933/Z0930 on glutamate kinase and therefore rendered the pathogen unsusceptible to killing by the drug. It was further proposed that the mutation site could be within the drug binding site. This study demonstrates, for the first time, the feasibility of small molecule-induced enhancement, but not inhibition, of enzymatic activities of a particular metabolic pathway as a workable strategy for the identification of anti-TB drugs.
   

This study highlights: 1) the identification of glutamate kinase as new anti-TB drug target, 2) the development of anti-TB agents with novel modes of action by optimizing quinolines, and 3) the potential value of enzymatic enhancers, but not only inhibitors, as effective drugs in target-based drug screening approach.
   

This study was funded by two projects from Chinese Academy of Sciences (154144KYSB20150045 and YJKYYQ20170036), and partially by Guangdong Marine Economic Development project (GDME-2018C003) and State Key Laboratory of Respiratory Disease projects (SKLRD2016ZJ003 and SKLRD-OP-201919). Gaelle G. Makafe and Chiwala Gift were funded by CAS-TWAS. Goverdhan Surineni received funds from CAS-PIFI and Huangpu district post-doctoral program. Tianyu Zhang was supported by Guangdong special support plan.