Nitrogen metabolism in mycobacteria: the key genes and targeted antimicrobials

Abstract

Nitrogen metabolism is an important physiological process that affects the survival and virulence of Mycobacterium tuberculosis. M. tuberculosis’s utilization of nitrogen in the environment and its adaptation to the harsh environment of acid and low oxygen in macrophages are closely related to nitrogen metabolism. In addition, the dormancy state and drug resistance of M. tuberculosis are closely related to nitrogen metabolism. Although nitrogen metabolism is so important, limited research was performed on nitrogen metabolism as compared with carbon metabolism. M. tuberculosis can use a variety of inorganic or organic nitrogen sources, including ammonium salts, nitrate, glutamine, asparagine, etc. In these metabolic pathways, some enzymes encoded by key genes, such as GlnA1, AnsP2, etc, play important regulatory roles in the pathogenesis of TB. Although various small molecule inhibitors and drugs have been developed for different nitrogen metabolism processes, however, long-term validation is needed before their practical application. Most importantly, with the emergence of multidrug-resistant strains, eradication, and control of M. tuberculosis will still be very challenging.

Amino Acid Biosynthesis Inhibitors in Tuberculosis Drug Discovery

“…In the past five years, the multifaceted bactericidal mechanism of amino acid starvation has gained considerable attention, and a better understanding of amino acid biosynthetic pathways has paved the way for target-based screenings against defined protein targets of the pathways. Many inhibitors of key enzymes of several amino acid biosynthetic pathways have been discovered, proving their chemical vulnerability and providing optimism for future advances [ 95 ]. While several studies have reported nanomolar enzymatic inhibitions, there is still a lack of cell and animal experiments.…”

“…Indeed, an Mtb mutant lacking the encoding gene ansA shows impaired nitrogen incorporation from Asn and has attenuated virulence in interferon gamma (IFN-γ)-activated macrophages and in mice [9]. Nonetheless, compared to other metabolic enzymes involved in nitrogen metabolism, those belonging to Ans metabolism are largely unexplored [95]. The only study highlighting the potential role of asparaginase as a potential drug target reports a three-dimensional structural model via the SWISS-MODEL server (http://swissmodel.expasy.org/) using P. horikoshi L.-asparaginase as a structure template (percentage of sequence identity equal to 27%).…”

“…Ans and Asp are among the major sources of nitrogen for Mtb . The mycobacterium mainly exploits Ans from host tissues through the transporter AnsP1 and the paralogue AnsP2 ( Rv0346c ), which are involved in Asp and Ans uptake in the mycobacterial phagosome [ 9 , 95 ]. Even though AnsP2 is not responsible for virulence, ansP2 expression is strongly induced in the lungs of TB patients, which could reflect the importance of this transporter.…”

The <em>Mycobacterium tuberculosis</em>: A Silent Killer

“…Sulfur in turn is important for the initial process of protein synthesis and for maintaining a redox environment. Therefore, these metabolic systems in MTB present several proteins related to the detection of critical concentrations, capture and transformation of organic and inorganic sources in the molecules of interest [114,[117][118][119][120][121][122][123][124].…”