Abstract
Mycobacterium tuberculosis is a human pathogen that can thrive inside the host immune cells for several years and cause tuberculosis. This is due to the propensity of M. tuberculosis to synthesize a sturdy cell wall, shift metabolism and growth, secrete virulence factors to manipulate host immunity, and exhibit stringent response. These attributes help M. tuberculosis to manage the host response, and successfully establish and maintain an infection even under nutrient-deprived stress conditions for years. In this review, we will discuss the importance of mycobacterial stringent response under different stress conditions. The stringent response is mediated through small signaling molecules called alarmones “(pp)pGpp”. The synthesis and degradation of these alarmones in mycobacteria are mediated by Rel protein, which is both (p)ppGpp synthetase and hydrolase. Rel is important for all central dogma processes—DNA replication, transcription, and translation—in addition to regulating virulence, drug resistance, and biofilm formation. Rel also plays an important role in the latent infection of M. tuberculosis. Here, we have discussed the literature on alarmones and Rel proteins in mycobacteria and highlight that (p)ppGpp-analogs and Rel inhibitors could be designed and used as antimycobacterial compounds against M. tuberculosis and non-tuberculous mycobacterial infections.
Highlights
1need to shorten the duration of TB treatment and contain the threat of drug-resistant TB. These two aims can be rapidly achieved by targeting the stringent response, which regulates persistence, drug resistance, and biofilm formation in several bacterial pathogens [16,41,42], Pathogens 2021, 10, 1417 though there is limited information on mycobacteria
We present an overview of the stringent response in mycobacteria and describe the metabolism of all three alarmones—
We have described how stringent response regulates long-term survival, pathogenesis, virulence, antibiotic resistance, and biofilm formation in M. tuberculosis and
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. 1need to shorten the duration of TB treatment and contain the threat of drug-resistant TB These two aims can be rapidly achieved by targeting the stringent response, which regulates persistence, drug resistance, and biofilm formation in several bacterial pathogens [16,41,42], Pathogens 2021, 10, 1417 though there is limited information on mycobacteria. Several bacteria including mycobacteria encode homologs of RSH proteins, which are smaller in length These proteins are usually single-domain proteins and possess either synthetase or hydrolase activity. M. smegmatis encodes RelZ, a SAS protein, which can synthesize the third alarmone, pGpp, unlike its M. tuberculosis ortholog Rv1366 (Figure 1). No SAH has been identified in mycobacteria, RelMsm cleaves pGpp to GMP and pyrophosphate [30] (Figure 1B)
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