Mutations and insights into the molecular mechanisms of resistance of Mycobacterium tuberculosis to first-line drugs

Abstract

Genetically antimicrobial resistance in Mycobacterium tuberculosis is currently one of the most important aspects of tuberculosis, considering that there are emerging resistant strains for almost every known drug used for its treatment. There are multiple antimicrobials used for tuberculosis treatment, and the most effective ones are the first-line drugs, which include isoniazid, pyrazinamide, rifampicin, and ethambutol. In this context, understanding the mechanisms of action and resistance of these molecules is essential for proposing new therapies and strategies of treatment. Additionally, understanding how and where mutations arise conferring a resistance profile to the bacteria and their effect on bacterial metabolism is an important requisite to be taken in producing safer and less susceptible drugs to the emergence of resistance. In this review, we summarize the most recent literature regarding novel mutations reported between 2017 and 2022 and the advances in the molecular mechanisms of action and resistance against first-line drugs used in tuberculosis treatment, highlighting recent findings in pyrazinamide resistance involving PanD and, additionally, resistance-conferring mutations for novel drugs such as bedaquiline, pretomanid, delamanid and linezolid.