Stringent Response in Mycobacteria: From Biology to Therapeutic Potential

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.

Protein–Ligand Interactions in Scarcity: The Stringent Response from Bacteria to Metazoa, and the Unanswered Questions

“…A detailed analysis of the binding mode of ppGpp should await actual crystal structures. Nevertheless, these studies will be relevant for M. tuberculosis as well, as this important human pathogen also has a robust stringent response regulated by ppGpp, reviewed recently [ 132 ].…”

Antibiotic Resistance to Mycobacterium tuberculosis and Potential Use of Natural and Biological Products as Alternative Anti-Mycobacterial Agents

“…In addition, PE-PGRS proteins of Mtb allow its survival in the granuloma, as well as its interaction with host cells [ 82 , 83 , 84 ]. Deletion of Rel affects Mtb survival or inhibits its growth [ 10 , 85 ]. In fact, the H37Rv delta-Rel-Mtb causes a mild form of lung TB with few granulomas and organ architecture still conserved in comparison to the parental strain, H37rv, which causes a serious pulmonary damage in mice [ 86 ].…”

“…Thus, a prolonged drug administration is implied, which may lead to the development of MDR strains [ 9 ]. In fact, under hostile circumstances, Mtb demonstrates the so-called stringent response for surviving [ 10 ]. This type of response is mediated by alarmones, which regulate fundamental bacterial processes, such as replication, transcription, and translation [ 11 , 12 ].…”

DMNP, a Synthetic Analog of Erogorgiaene, Inhibits the ppGpp Synthetase Activity of the Small Alarmone Synthetase RelZ

“…Thus, to resolve the problem of bacterial persistence, novel and more effective treatment strategies are required. One of the possible ways to solve it may be the development of new compounds that compromise bacterial adaptations to stress, such as the stringent response [1,9], the synthesis of (p)ppGpp alarmones signaling molecules, which act as positive regulators of bacterial persistence [10].…”

“…Alarmone synthetase inhibitors present a new strategy for the treatment of tuberculosis [1,9]. Research on the drug class having this mode of action began with relacin and its analogs, which are modified variants of (p)ppGpp that block wide range of long RSH proteins [15,16].…”