Development of macrocyclic peptide inhibitors of Mycobacterium tuberculosis MurF via mRNA display with genetic reprogramming.

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.