Inhibition of glutamine synthetase: a potential drug target in Mycobacterium tuberculosis.

Sherry Mowbray,Abhishek Pandey,Luke Odell,Muthu Kathiravan

doi:10.3390/molecules190913161

Abstract

Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis. Globally, tuberculosis is second only to AIDS in mortality and the disease is responsible for over 1.3 million deaths each year. The impractically long treatment schedules (generally 6–9 months) and unpleasant side effects of the current drugs often lead to poor patient compliance, which in turn has resulted in the emergence of multi-, extensively- and totally-drug resistant strains. The development of new classes of anti-tuberculosis drugs and new drug targets is of global importance, since attacking the bacterium using multiple strategies provides the best means to prevent resistance. This review presents an overview of the various strategies and compounds utilized to inhibit glutamine synthetase, a promising target for the development of drugs for TB therapy.

Highlights

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis
Though drugs of diverse chemical structures acting through different mechanisms are available for the treatment of M. tuberculosis, there are still many problems associated with the currently available compounds
This review presents an overview of the various strategies and compounds utilized to inhibit glutamine synthetase, a promising target for the development of drugs for TB therapy

Summary

Introduction

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis. The World. TB is a disease with close socioeconomic links, since it attacks a disproportionate number of young adults, and flourishes in the context of poverty It is curable in most cases, but the impractically long treatment schedules (generally 6–9 months) and unpleasant side effects of the current drugs often lead to poor patient compliance, which in turn has resulted in the emergence of multidrug resistant (MDR-TB) strains. Like other bacterial glutamine synthetases, MtGS is a dodecamer formed of two hexameric rings stacked on top of each other; each active site includes contributions from two adjacent subunits within a ring [10]. An enzyme-bound ammonium ion is deprotonated, forming ammonia that attacks the carbonyl carbon of γ-glutamyl phosphate to form a tetrahedral intermediate (II). The strand shift creates a very different environment in the nucleotide, ammonium, and metal-binding sites, and so explains the large effects on enzyme activity

Inhibitors of GS

Amino Acid Analogues

Purine Analogues as Novel ATP-Competitive Inhibitors

Potential ATP-Competitive Inhibitors

Conclusions