Control of Mycobacterium tuberculosis infection continues to be an issue, particularly in countries with a high tuberculosis (TB) burden in the tropical and sub-tropical regions. The effort to reduce the catastrophic cost of TB with the WHO’s End TB Strategy in 2035 is still obstructed by the emergence of drug-resistant TB (DR-TB) cases as result of various mutations of the MTB strain. In the approach to combat DR-TB, several potential antitubercular agents were discovered as inhibitors for various existing and novel targets. Host-directed therapy and immunotherapy also gained attention as the drug-susceptibility level of the pathogen can be reduced due to the pathogen’s evolutionary dynamics. This review is focused on the current progress and challenges in DR-TB treatment. We briefly summarized antitubercular compounds that are under development and trials for both DR-TB drug candidates and host-directed therapy. We also highlighted several problems in DR-TB diagnosis, the treatment regimen, and drug discovery that have an impact on treatment adherence and treatment failure.

Mycobacterium tuberculosis (MTB) is the main source of tuberculosis (TB), one of the oldest known diseases in the human population. Despite the drug discovery efforts of past decades, TB is still one of the leading causes of mortality and claimed more than 1.5 million lives worldwide in 2020. Due to the emergence of drug-resistant strains and patient non-compliance during treatments, there is a pressing need to find alternative therapeutic agents for TB. One of the important areas for developing new treatments is in the inhibition of the transcription step of gene expression; it is the first step to synthesize a copy of the genetic material in the form of mRNA. This further translates to functional protein synthesis, which is crucial for the bacteria living processes. MTB contains a bacterial DNA-dependent RNA polymerase (RNAP), which is the key enzyme for the transcription process. MTB RNAP has been targeted for designing and developing antitubercular agents because gene transcription is essential for the mycobacteria survival. Initiation, elongation, and termination are the three important sequential steps in the transcription process. Each step is complex and highly regulated, involving multiple transcription factors. This review is focused on the MTB transcription machinery, especially in the nature of MTB RNAP as the main enzyme that is regulated by transcription factors. The mechanism and conformational dynamics that occur during transcription are discussed and summarized. Finally, the current progress on MTB transcription inhibition and possible drug target in mycobacterial RNAP are also described to provide insight for future antitubercular drug design and development.

Tuberculosis (TB) remains one of the deadliest infectious diseases in the world. Although several established antitubercular drugs have been found, various factors obstruct efforts to combat this disease due to the existence of drug-resistance (DR) TB strains, the need for lengthy treatment, and the occurrence of side effects from drug–drug interactions. Rifampicin (RIF) is the first line of antitubercular drugs and targets RNA polymerase (RNAP) of Mycobacterium tuberculosis (MTB). Here, RIF blocks the synthesis of long RNA during transcription initiation. The efficacy of RIF is low in DR-TB strains, and the use of RIF leads to various side effects. In this study, novel cyclic peptides were computationally designed as inhibitors of MTB transcription initiation. The designed cyclic peptides were subjected to a virtual screening to generate compounds that can bind to the RIF binding site in MTB RNAP subunit β (RpoB) for obtaining a new potential TB drug with a safe clinical profile. The molecular simulations showed that the cyclic peptides were capable of binding with RpoB mutants, suggesting that they can be possibility utilized for treating DR-TB. Structural modifications were carried out by acetylation and amidation of the N- and C-terminus, respectively, to improve their plasma stability and bioavailability. The modified linear and cyclic peptides were successfully synthesized with a solid-phase peptide synthesis method using Fmoc chemistry, and they were characterized by analytical HPLC, LC-ESI-MS⁺, and 1H NMR.