The development of new antibacterials for Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), remains critical due to the continued global burden of disease and the emergence of multi-drug resistant (MDR-TB) and extensively drug-resistant (XDR-TB) strains. The MurF enzyme, which catalyses the ATP-dependent ligation of d-Ala-d-Ala to a UDP-MurNAc-tripeptide precursor in peptidoglycan biosynthesis, represents a promising therapeutic target. In this work, random non-standard peptide integrated discovery (RaPID) mRNA display with genetic reprogramming of a non-canonical uracil-derived amino acid was applied to Mtb MurF, leading to the identification of several high-affinity thioether-linked cyclic peptide ligands, several of which also inhibited the catalytic activity of the Mtb MurX enzyme.
These findings provide a mechanistic rationale for MtbCBS inhibition, and the unexplored roles of these key residues can be considered in the design of next-generation inhibitors targeting CBS enzymes implicated in infectious diseases, cancer, and neurological disorders.
Sainath Polepalli, Anupam Roy, Bapan Mondal et al.· International Journal of Bio...· 0 citations
Tuberculosis (TB) is a severe airborne infectious disease caused by
Mycobacterium tuberculosis
(
M. tb
), primarily impacting the lungs and other organs. Antimicrobial resistance in TB is an emerging problem that requires immediate treatment and management. It is difficult to cure tuberculosis as there are increa...
Sandeep Bindra, Chetna Amrodiya, M. Abdelgawad et al.· Arabian Journal of Chemistry· 0 citations
The discovery of new therapeutic targets for combating tuberculosis has become crucial due to the alarming increase in multi-drug resistant strains. The acyltransferase PatA, involved in the biosynthesis of phosphatidyl-myo-inositol mannosides (PIMs), key components of the mycobacterial cell wall, has recently been sho...
These findings establish BVL3572S as a promising lead compound acting through a previously unexploited, multitarget mechanism, and display strong synergy with the antitubercular drug D-cycloserine.
Zainab Edoo, Astrid Lenne-Delmotte, C. Grosse et al.· Cell Chemical Biology· 0 citations
Bacterial tRNA-(N1G37) methyltransferase (TrmD), a member of the SPOUT superfamily, plays a pivotal role in catalyzing the methyl group transfer from S-adenosyl-l-methionine to the N1 position of G37 in the pathway of post-transcriptional modifications of bacterial tRNA. In response to the urgent global clinical need...
Zhi-Wei Meng, Dian-Fu Xia, Xin-Tong Zhang et al.· Journal of Medicinal Chemist...· 0 citations
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a major global health concern, particularly due to the emergence of drug-resistant strains. FAD-containing monooxygenase EthA activates the antitubercular prodrug ethionamide (ETH) in Mtb. However, the structural and functional mechanisms of Mtb Eth...
