Structural, functional and biological insights into the role of Mycobacterium tuberculosis VapBC11 toxin-antitoxin system: targeting a tRNase to tackle mycobacterial adaptation.

摘要: Toxin-antitoxin (TA) systems are involved in diverse physiological processes prokaryotes, but their exact role Mycobacterium tuberculosis (Mtb) virulence and vivo stress adaptation has not been extensively studied. Here, we demonstrate that the VapBC11 TA module is essential for Mtb to establish infection guinea pigs. RNA-sequencing revealed overexpression of VapC11 toxin results metabolic slowdown, suggesting modulation growth rate an strategy survival. Interestingly, resulted upregulation chromosomal genes, existence highly coordinated crosstalk among systems. In this study, also present crystal structure heterooctameric complex at 1.67 A resolution. Binding kinetic studies suggest binding affinities toxin-substrate toxin-antitoxin interactions comparable. We used a combination structural studies, molecular docking, mutational analysis vitro ribonuclease assays enhance our understanding mode substrate recognition by toxin. Furthermore, have designed peptide-based inhibitors target activity. Taken together, propose structure-guided design against ribonucleases might be novel hasten clearance intracellular Mtb.