Role of post‐translational modifications in the acquisition of drug resistance in Mycobacterium tuberculosis

Abstract

Tuberculosis (TB) is one of the primary causes of deaths due to infectious diseases. The current TB regimen is long and complex, failing of which leads to relapse and/or the emergence of drug resistance. There is a critical need to understand the mechanisms of resistance development. With increasing drug pressure, Mycobacterium tuberculosis (Mtb) activates various pathways to counter drug-related toxicity. Signaling modules steer the evolution of Mtb to a variant that can survive, persist, adapt, and emerge as a form that is resistant to one or more drugs. Recent studies reveal that about 1/3rd of the annotated Mtb proteome is modified post-translationally, with a large number of these proteins being essential for mycobacterial survival. Post-translational modifications (PTMs) such as phosphorylation, acetylation, and pupylation play a salient role in mycobacterial virulence, pathogenesis, and metabolism. The role of many other PTMs is still emerging. Understanding the signaling pathways and PTMs may assist clinical strategies and drug development for Mtb. In this review, we explore the contribution of PTMs to mycobacterial physiology, describe the related cellular processes, and discuss how these processes are linked to drug resistance. A significant number of drug targets, InhA, RpoB, EmbR, and KatG, are modified at multiple residues via PTMs. A better understanding of drug-resistance regulons and associated PTMs will aid in developing effective drugs against TB.

Artificial Intelligence in Surveillance, Diagnosis, Drug Discovery and Vaccine Development against COVID-19

“…The computational approaches have proven very effective in basic research, diagnosis, and treatment to fight against infectious diseases [ 54 , 226 , 227 , 228 , 229 , 230 , 231 , 232 , 233 ]. AI-based approaches have emerged as a useful tool/method in surveillance, diagnostic and discovery of new therapeutics [ 139 , 187 , 224 , 234 ] ( Figure 2 ).…”

Stringent Response in Mycobacteria: From Biology to Therapeutic Potential

“…Bacteria encounter constantly changing environments that may threaten their survival and existence; hence, it is particularly important to study their survival strategies in different model systems [1][2][3]. These strategies include several sensory mechanisms and signaling pathways that are required to overcome such threats [4][5][6][7][8][9]. These mechanisms help bacteria to sense the environmental cues and generate an appropriate adaptive response.…”

“…However, the treatment may last up to two years in the case of drug-resistant TB. Drug-resistant TB also poses a serious threat to public health due to its contagious nature and spectrum of drug-resistance [8,[38][39][40]. Hence, there is an urgent need to shorten the duration of TB treatment and contain the threat of drug-resistant TB.…”

Rv0802c is an acyltransferase that succinylates and acetylates Mycobacterium tuberculosis nucleoid-associated protein HU

“…However, studies on how the epigenetic changes influence the physiology in prokaryotic systems are emerging now. Various mycobacterial proteins and membrane constituents undergo PTMs [33][34][35][36][37][38][39][40][41][42][43][44]. Given the presence of unique C-terminal extension rich in lysine residues, we considered the possibility of MtHU as a potential target for PTMs.…”