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

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.

Mycobacterium tuberculosis: Pathogenesis and therapeutic targets

“…This not only complicates the treatment and management of TB but also poses a significant threat to global health. 495 Consequently, any new therapeutic strategy must prioritize the circumvention of any crosstalk or interaction with first-line drugs whilst simultaneously minimizing the risk of inducing resistance to existing therapies. Achieving this goal necessitates not only exhaustive characterization of current resistance mechanisms and the establishment of effective strategies to circumvent any potential cross-resistance, but also the identification and validation of novel biological targets, and action mechanisms and potent lead compounds with novel scaffold to guide subsequent preclinical research and development initiatives.…”

“…It is disappointing that the occurrence of drug‐resistant genes and multidrug‐resistant strains of Mtb is distressingly common. This not only complicates the treatment and management of TB but also poses a significant threat to global health 495 . Consequently, any new therapeutic strategy must prioritize the circumvention of any crosstalk or interaction with first‐line drugs whilst simultaneously minimizing the risk of inducing resistance to existing therapies.…”