Studies have found that enhancing glutamate kinase activity kills tuberculosis

Studies have found that enhancing glutamate kinase activity kills tuberculosis

June 27, 2019 Source: Science Network

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Schematic diagram of the mechanism of action to kill Mtb.

Zhang Tianyu and Liu Jinsong of the Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, in collaboration with the Guangzhou Chest Hospital, the Shenzhen Third People's Hospital, and the University of Albanova, Sweden, have found that enhancing, but not inhibiting, glutamate kinase , GK) activity can kill Mycobacterium tuberculosis (Mtb), referred to as tuberculosis. Related research was published online June 14 in Cell-Chemical Biology. It is reported that Zhang Jiancun and Zhu Qiang's research group have given great assistance.

Tuberculosis (TB) is a fatal disease caused by Mtb. According to data released by the World Health Organization since 2016, TB has re-emerged as the world's largest infectious disease, with more than 10 million new cases each year, and the number of deaths continues to be 1.6 million.

"In recent years, with the co-infection of drug-resistant Mtb, Mtb and HIV, and the increase in Mtb infection in other immunocompromised populations, TB has revived. For this reason, it is extremely urgent to develop new anti-TB drugs with high efficiency and low toxicity." Zhang Tianyu said. At present, the strategies for targeted screening of anti-TB drugs are almost always to find inhibitors of Mtb's key metabolic enzymes.

Researchers have found that GK may become a new target for anti-TB drugs. The new quinoline compound Z0930/Z0933 acts as a prodrug. Its active form enhances the feedback inhibition of the proline synthesis pathway by competing with proline to bind GK to enhance the activity of GK, but also affects the electron transport chain, resulting in excessive reactive oxygen species (ROS). To kill Mtb. The mutated GK activity is unaffected by the compound Z0930/Z0933, resulting in Mtb being able to tolerate higher concentrations of such compounds. The mutation point A226S of GK may be located at the Z0930/Z0933 binding site.

This study reveals that GK may become a new target for anti-TB drugs; compounds that target GK have been optimized and engineered to develop anti-Mtb drug candidates with novel mechanisms; target-based anti-TB drug discovery strategies should not be merely Screening inhibitors, enzyme activity enhancers are also expected to become new drugs.

It is known that this study is the first to report that small molecule enhancement rather than inhibition of metabolic enzyme activity can be a new strategy for potential anti-TB drugs.

Related paper information: https://doi.org/10.1016/j.chembiol.2019.05.003

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