Mycobacterial L,D-transpeptidase and D,D-transpeptidase

Mycobacterial L,D-transpeptidases and D,D-transpeptidases are two distinct families of enzymes responsible for the cross-linking of peptide side chains in the peptidoglycan layer of Mycobacterium tuberculosis and related mycobacteria. D,D-transpeptidases (also known as penicillin-binding proteins, PBPs) catalyze classical 4→3 cross-links, using a catalytic serine, while L,D-transpeptidases, relying on a catalytic cysteine, generate 3→3 cross-links which are predominant in mycobacteria. L,D-transpeptidases, particularly the paralog LdtMt2, are critical for the pathogenicity, viability, and resistance of M. tuberculosis, especially under non-replicating or latent conditions where classical PBPs are less active. Both enzyme families are validated therapeutic targets: L,D-transpeptidases are potently inhibited by carbapenem antibiotics (e.g., meropenem, imipenem), which form a covalent adduct with the active-site cysteine. However, standard penicillins and cephalosporins are generally ineffective due to poor binding and inactivation by mycobacterial β-lactamases, though newer probes and carbapenem combinations are being assessed. Loss or inhibition of L,D-transpeptidase activity compromises cell wall integrity and increases susceptibility to osmotic shock and certain antibiotics, supporting their status as essential and high-value drug targets in tuberculosis therapy.

Other names

LdtMt2 (major L,D-transpeptidase in Mycobacterium tuberculosis)Penicillin-binding protein (PBP, for D,D-transpeptidase subfamily)LdtMt (general abbreviation for Mycobacterial L,D-transpeptidases)

Inhibition of enzymatic cross-linking of peptidoglycan leading to bactericidal activity through disruption of cell wall integrity.