Understanding the role of PezAT and MbcTA toxin-antitoxin systems in the pathophysiology of Mycobacterium tuberculosis.

Abstract

Toxin antitoxin (TA) systems are bicistronic genetic elements encoding for a stable toxin and its cognate labile antitoxin. The genome of Mycobacterium tuberculosis (M. tuberculosis) encodes a large repertoire of TA systems and these are highly conserved in members of the M. tuberculosis complex. In the present study, we have characterised PezAT and MbcTA TA systems from M. tuberculosis. We show that the transcript levels of toxins and antitoxins belonging to PezAT and MbcTA were increased in M. tuberculosis exposed to oxidative stress, nitrosative stress and rifampicin. We also show that the relative levels of precursors for the peptidoglycan biosynthesis were increased in the PezT overexpression strain of M. smegmatis relative to uninduced cultures. Here, we have used temperature-sensitive mycobacteriophages to generate ΔpezAT and ΔmbcT mutant strains of M. tuberculosis. We demonstrate that the deletion of pezAT reduced the growth of M. tuberculosis upon exposure to detergent stress or rifampicin. However, the deletion of mbcT does not affect M. tuberculosis growth in various stress conditions. We also report that both PezAT and MbcT are dispensable for M. tuberculosis growth in macrophages and guinea pigs. Overall, these findings suggest that functional redundancy exists between TA systems.