Death of Mycobacterium tuberculosis by l-arginine starvation.

Death of Mycobacterium tuberculosis by l-arginine starvation. Mizrahi, V. & Warner, D. F Proceedings of the National Academy of Sciences of the United States of America, 115(39):9658–9660, National Academy of Sciences, sep, 2018.

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Tuberculosis (TB) is currently the leading cause of mortality from a single infectious agent, resulting in more than 1.5 million deaths annually. In 2016, 10.4 million people developed the disease (1), of whom 490,000 had multidrug-resistant TB, defined as resistant to the two first-line drugs, isoniazid (INH) and rifampicin. Given that combination chemotherapies against the causative agent, Mycobacterium tuberculosis ( Mtb ), form the cornerstone of TB control, these stark statistics underscore the urgent need for new drugs to tackle this global health scourge. In response to this need, a pipeline has been established that has begun to deliver new and repurposed TB drugs (2). Key attributes for new drugs include efficacy against drug-resistant as well as drug-sensitive TB and an ability to effect a rapid, relapse-free (i.e., sterilizing) cure. These requirements have placed a high premium on the identification and validation of new targets, which differ from those of existing TB drugs, coupled with the development of potent compounds that will kill Mtb rapidly upon target engagement. This is a tall order for a notoriously underresourced field of research (3). In PNAS, Tiwari et al. (4) contribute to this endeavor by reporting the identification of two promising new TB drug targets: acetyl glutamate kinase (ArgB) and ornithine carbamoyl transferase (ArgF). These enzymes catalyze the second and sixth steps, respectively, in the pathway for the de novo biosynthesis of the amino acid l-arginine, from l-glutamate in Mtb (Fig. 1). The work of Tiwari et al. began with the observation that a feature common to the mycobactericidal agents, INH and vitamin C, is an ability to kill Mtb rapidly via a mechanism associated with the production of reactive oxygen species (ROS) (5). Using transcriptional profiling to investigate the effects of INH and vitamin C exposure on mycobacterial cellular metabolism, Tiwari … [↵][1]1To whom correspondence should be addressed. Email: valerie.mizrahi\at\uct.ac.za. [1]: #xref-corresp-1-1

@article{Mizrahi2018,
abstract = {Tuberculosis (TB) is currently the leading cause of mortality from a single infectious agent, resulting in more than 1.5 million deaths annually. In 2016, 10.4 million people developed the disease (1), of whom 490,000 had multidrug-resistant TB, defined as resistant to the two first-line drugs, isoniazid (INH) and rifampicin. Given that combination chemotherapies against the causative agent, Mycobacterium tuberculosis ( Mtb ), form the cornerstone of TB control, these stark statistics underscore the urgent need for new drugs to tackle this global health scourge. In response to this need, a pipeline has been established that has begun to deliver new and repurposed TB drugs (2). Key attributes for new drugs include efficacy against drug-resistant as well as drug-sensitive TB and an ability to effect a rapid, relapse-free (i.e., sterilizing) cure. These requirements have placed a high premium on the identification and validation of new targets, which differ from those of existing TB drugs, coupled with the development of potent compounds that will kill Mtb rapidly upon target engagement. This is a tall order for a notoriously underresourced field of research (3). In PNAS, Tiwari et al. (4) contribute to this endeavor by reporting the identification of two promising new TB drug targets: acetyl glutamate kinase (ArgB) and ornithine carbamoyl transferase (ArgF). These enzymes catalyze the second and sixth steps, respectively, in the pathway for the de novo biosynthesis of the amino acid l-arginine, from l-glutamate in Mtb (Fig. 1). The work of Tiwari et al. began with the observation that a feature common to the mycobactericidal agents, INH and vitamin C, is an ability to kill Mtb rapidly via a mechanism associated with the production of reactive oxygen species (ROS) (5). Using transcriptional profiling to investigate the effects of INH and vitamin C exposure on mycobacterial cellular metabolism, Tiwari {\ldots} [↵][1]1To whom correspondence should be addressed. Email: valerie.mizrahi{\{}at{\}}uct.ac.za. [1]: {\#}xref-corresp-1-1},
author = {Mizrahi, Valerie and Warner, Digby F},
doi = {10.1073/pnas.1813587115},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Mizrahi, Warner - 2018 - Death of Mycobacterium tuberculosis by l-arginine starvation.pdf:pdf},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
keywords = {OA,commentary,fund{\_}not{\_}ack},
mendeley-tags = {OA,commentary,fund{\_}not{\_}ack},
month = {sep},
number = {39},
pages = {9658--9660},
pmid = {30190428},
publisher = {National Academy of Sciences},
title = {{Death of \textit{Mycobacterium tuberculosis} by l-arginine starvation.}},
url = {http://www.ncbi.nlm.nih.gov/pubmed/30190428 http://www.pnas.org/content/early/2018/09/05/1813587115},
volume = {115},
year = {2018}
}

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