Protein synthesis is a fundamental requirement of all cells for survival and replication. To date, vast numbers of genetic and biochemical studies have been performed to address the mechanisms of translation and its regulation in Escherichia coli, but only a limited number of studies have investigated these processes in other bacteria, particularly in slow growing bacteria like Mycobacterium tuberculosis, the causative agent of human tuberculosis. In this Review, we highlight important differences in the translational machinery of M. tuberculosis compared with E. coli, specifically the presence of two additional proteins and subunit stabilizing elements such as the B9 bridge. We also consider the role of leaderless translation in the ability of M. tuberculosis to establish latent infection and look at the experimental evidence that translational regulatory mechanisms operate in mycobacteria during stress adaptation, particularly focussing on differences in toxin-antitoxin systems between E. coli and M. tuberculosis and on the role of tuneable translational fidelity in conferring phenotypic antibiotic resistance. Finally, we consider the implications of these differences in the context of the biological adaptation of M. tuberculosis and discuss how these regulatory mechanisms could aid in the development of novel therapeutics for tuberculosis.
Our work ” Delayed effects of transcriptional responses in Mycobacterium tuberculosis exposed to nitric oxide suggest other mechanisms involved in survival” has been published in Scientific Reports.
Bacterial adaptation to stress has been commonly studied in the context of transcriptional responses, with the implicit assumption that transcriptional changes are tightly coupled with protein changes. Here, we have challenged M. tuberculosis with nitric oxide and interrogated the dynamic transcriptome and proteome response through time resolved analysis. The first main finding of this study is that despite an immediate transcriptomic response to nitric oxide, transcriptional changes take several hours to manifest on the protein level, demonstrating an overall delay in protein production in response to nitric oxide. The second main finding is that early changes in the proteome are characterised by degradation of a specific set of proteins rather than by synthesis of new proteins, highlighting a discordance between the transcriptome and proteome. Overall, our findings suggest that whilst the early transcriptome changes might contribute to late-stage recovery, the initial resistance and survival of M. tuberculosis to nitric oxide is contingent on mechanisms other than transcriptional regulation.
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