A consequence of drug targeting of aminoacyl‐tRNA synthetases in Mycobacteriumtuberculosis

Abstract

Drug‐resistant Mycobacterium tuberculosis poses a great threat to public health and remains one of the red‐flag tagged infectious diseases, with the tendency of comorbidity with other disease conditions such as HIV/AIDS. This perhaps is responsible for redoubling of effort in tuberculosis research and continuous change in patient management to optimize the drug therapy. Aminoacyl‐tRNA synthetases are essential enzymes in M. tuberculosis that catalyse the transfer of a particular amino acid to its corresponding specific tRNA to form an aminoacyl‐tRNA. These enzymes are believed to be novel antibacterial, antifungal and antiparasitic drug targets because of their role in the process of protein translation. Therefore, their existence as a compliment of M. tuberculosis has attracted a lot of research interest with the aim of curbing the scourge and provide the most effective drug in the treatment of tuberculosis. This leads to the discovery of a pool of aminoacyl‐tRNA synthetases with their essential inhibitors. This review seeks to articulate the current advances in the development of new TB drugs exhibiting novelty in their mode of action with specific emphasis on aminoacyl‐tRNA synthetases as drug targets.

Antimalarial drug discovery: progress and approaches

“…These targets have been well validated and a number of them are now structurally characterized 105 , 107 , 108 . The tRNA synthetase class also appears to be an important target class in other pathogens such as Mycobacterium tuberculosis 109 , Leishmania species 110 , 111 and T. gondii 112 , 113 , and tool compounds show specificity despite orthologs existing in humans. The high level of species selectivity might be achieved because, in humans, tRNA synthetases are part of multiprotein complexes and the enzyme active site is less accessible and thus less druggable.…”

Tavaborole-Induced Inhibition of the Aminoacyl-tRNA Biosynthesis Pathway against Botrytis cinerea Contributes to Disease Control and Fruit Quality Preservation

“…As a result, in order to deal with the availability of extracellular and intracellular amino acids in conjunction with various cellular processes, cells must develop complex sensing mechanisms. Notably, leucyl-tRNA synthetase 1 and glutaminyl-tRNA synthetase 1 have been shown to sense and transmit signals related to intracellular levels of their cognate amino acids. ,− Thus, inhibiting the activities of ARSs results in the termination of protein synthesis, which inhibits fungal growth, and aminoacyl-tRNA synthetases are thought to be novel antibacterial, antifungal, and antiparasitic drug targets. ,, GSK3036656, a boron-containing molecule that targets the editing domain of Mycobacterium tuberculosis LeuRS, was recently synthesized and preclinically evaluated . ARSs can bind to their cognate amino acids and thus play important roles in protein interactions.…”

“…42,50−53 Thus, inhibiting the activities of ARSs results in the termination of protein synthesis, which inhibits fungal growth, 41 and aminoacyl-tRNA synthetases are thought to be novel antibacterial, antifungal, and antiparasitic drug targets. 41,43,54 GSK3036656, a boron-containing molecule that targets the editing domain of Mycobacterium tuberculosis LeuRS, was recently synthesized and preclinically evaluated. 55 ARSs can bind to their cognate amino acids and thus play important roles in protein interactions.…”

Insights into the Effects of Ligand Binding on Leucyl-tRNA Synthetase Inhibitors for Tuberculosis: In Silico Analysis and Isothermal Titration Calorimetry Validation

“…Incidences of drug-resistant tuberculosis have become common and are rising at an alarming rate. The development of resistance and cross-resistance has always driven researchers to search for novel targets and drugs with new mechanisms to counter the drug resistance problem [ 2 , 3 ]. Aminoacyl t-RNA synthetases are ubiquitously found in all organisms and regulate the transcription process by playing an active role in protein biosynthesis.…”

“…Various benzoxaborole derivatives, like AN2690, ZCL039, GSK656, and EC/11770, have been discovered as potent inhibitors, amongst which GSK656 and EC/11770 possess antimycobacterial leucyl t-RNA synthetase [4,8] inhibition properties [9,10]. Some antimycobacterial leucyl t-RNA synthetase inhibitors amongst the N-Benzylidene-thiazol-2-yl-hydrazin [1] and 5-phenylamino-2H- [2,4]triazin-3-one derivatives have also been reported [11,12]. Figure 1 represents the known inhibitors against mycobacterial leucyl t-RNA synthetase.…”