6fkg

Publication Abstract from PubMed

Toxin-antitoxin (TA) systems regulate fundamental cellular processes in bacteria and represent potential therapeutic targets. We report a new RES-Xre TA system in multiple human pathogens, including Mycobacterium tuberculosis. The toxin, MbcT, is bactericidal unless neutralized by its antitoxin MbcA. To investigate the mechanism, we solved the 1.8 A-resolution crystal structure of the MbcTA complex. We found that MbcT resembles secreted NAD(+)-dependent bacterial exotoxins, such as diphtheria toxin. Indeed, MbcT catalyzes NAD(+) degradation in vitro and in vivo. Unexpectedly, the reaction is stimulated by inorganic phosphate, and our data reveal that MbcT is a NAD(+) phosphorylase. In the absence of MbcA, MbcT triggers rapid M. tuberculosis cell death, which reduces mycobacterial survival in macrophages and prolongs the survival of infected mice. Our study expands the molecular activities employed by bacterial TA modules and uncovers a new class of enzymes that could be exploited to treat tuberculosis and other infectious diseases.

An NAD(+) Phosphorylase Toxin Triggers Mycobacterium tuberculosis Cell Death.,Freire DM, Gutierrez C, Garza-Garcia A, Grabowska AD, Sala AJ, Ariyachaokun K, Panikova T, Beckham KSH, Colom A, Pogenberg V, Cianci M, Tuukkanen A, Boudehen YM, Peixoto A, Botella L, Svergun DI, Schnappinger D, Schneider TR, Genevaux P, de Carvalho LPS, Wilmanns M, Parret AHA, Neyrolles O Mol Cell. 2019 Feb 18. pii: S1097-2765(19)30048-6. doi:, 10.1016/j.molcel.2019.01.028. PMID:30792174^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.