Tuberculosis: toxins for new treatments?

Understand the role of toxin anti-toxin systems in Mycobacterium tuberculosis.

Tuberculosis is the leading cause of death due to a single infectious agent: bacteria. Mycobacterium tuberculosis. This bacteria mainly affects the lungs and is transmitted through the air. It can persist for a long time in the host in a non-replicating, drug-tolerant state, called latent tuberculosis. The emergence of multidrug-resistant and extensively antibiotic-resistant tuberculosis has greatly increased the need to identify new targets in order to develop new drugs and new treatment strategies.

A promising avenue is based on particular systems possessed by Mycobacterium tuberculosiscalled “toxin-antitoxin systems” (TA). These systems are genetic elements composed of a harmful toxin (the poison) and an antitoxin that inhibits its activity (the antidote). Under stressful conditions, inhibition by the antitoxin is lifted and active toxins can target essential cellular processes or structures such as protein synthesis (translation), replication, metabolism or cell wall synthesis, thus leading to growth inhibition or death of the bacillus. To date, we do not know the role of these TA systems in M. tuberculosis and the highly deleterious nature of certain toxins suggests that their antibacterial properties could be used to identify new therapeutic targets or directly as antimicrobial agents.

MenT3: a toxin of interest.

In an article published in Nature Communicationsscientists, have made an important discovery about one of these toxins called MenT3. This toxin blocks a process essential to the survival of bacteria: the production of proteins. It acts by modifying part of the transfer RNAs which are essential molecules for assembling proteins. To be more precise, it acts as a nucleotidyltransferase (NTase). This means that it controls the growth of Mycobacterium tuberculosis by blocking the production of proteins by a specific mechanism: it prevents the aminoacylation of transfer RNAs carrying serine, by modifying the end which receives this amino acid. Scientists have also discovered a mechanism by which the MenT3 toxin can be neutralized. Another enzyme, CCAse, which is also an NTase but this time involved in the maturation of transfer RNAs, can restore the ends of affected RNAs, thus allowing detoxification. Mycobacterium tuberculosis. This advance opens new perspectives for the development of innovative treatments based on the activation of the MenT3 toxin.