LDtranspeptidases

LDtranspeptidases, commonly written as L,D-transpeptidases (LDTs), are enzymes that mediate a unique form of peptidoglycan cross-linking in bacterial cell walls. Unlike the more prevalent D,D-transpeptidases that form 4→3 cross-links, LDTs catalyze the creation of 3–3 cross-links between the third residues of adjacent stem peptides, typically involving meso-diaminopimelic acid. The reaction relies on a cysteine-based catalytic mechanism, where an active-site cysteine forms an acyl-enzyme intermediate with the donor stem peptide and is then resolved by transfer to an acceptor stem peptide, yielding a direct covalent cross-link.

LDTs are widely distributed across bacteria, and their importance varies by species and growth conditions. In some pathogens, especially certain mycobacteria and enterococci, 3–3 cross-links contribute substantially to cell wall integrity and may compensate when D,D-transpeptidases are inhibited. This pathway can become particularly relevant under antibiotic pressure, influencing susceptibility to beta-lactams.

Clinical and research relevance centers on their role as antibiotic targets. LDTs can provide an alternative cross-linking route when D,D-transpeptidases are blocked, contributing to beta-lactam resistance in some contexts. Carbapenem antibiotics, among others, can inhibit LDTs, making them effective against LDT-dependent organisms and highlighting LDTs as attractive targets for novel antibacterial therapies. Ongoing research explores inhibitors that specifically block LDT activity and the resulting effects on bacterial cell wall integrity.

Notable examples include Ldt enzymes in Mycobacterium tuberculosis (LdtMt1, LdtMt2) and various LDTs identified across bacterial taxa.