Mycobacterium tuberculosisthe agent responsible for tuberculosis, produces toxins and their antidotes in order to regulate its growth and adapt to stress.
In an article published in Nature Communicationsscientists have described the mechanism of action of a toxins which blocks the production of proteins and showed how the cell could detoxify itself. These results open avenues for the implementation of treatments based onactivation of this toxin.
© Xibing Xu and Pierre Genevaux
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 deleterious toxin (the poison) and an antitoxin which 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, thereby leading to growth inhibition or mort 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 RNA 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 the serineby 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.
Reference:
Xu, X., Barriot, R., Voisin, B. et al.
Nucleotidyltransferase toxin MenT extends aminoacyl acceptor ends of serine tRNAs to control Mycobacterium tuberculosis growth.
Nat Common 15, 9596 (2024).
https://www.nature.com/articles/s41467-024-53931-w
