Bacterial L,D-transpeptidase (LDT)

Bacterial L,D-transpeptidases (LDTs) are enzymes essential for the synthesis and maintenance of the bacterial cell wall, specifically by catalyzing the formation of 3-3 peptidoglycan cross-links (PubMed: 22308237). While most bacteria primarily use D,D-transpeptidases (Penicillin-Binding Proteins or PBPs) to create 4-3 cross-links, certain pathogens like Mycobacterium tuberculosis and Enterococcus faecium rely heavily on LDTs for structural integrity and resistance to traditional antibiotics (PubMed: 19223571, 21949387). LDTs are structurally distinct from PBPs, utilizing a catalytic cysteine residue rather than a serine residue, which renders them naturally insensitive to many common beta-lactams such as penicillins and cephalosporins (PubMed: 23408779). However, carbapenems act as potent suicide substrates for LDTs, forming a stable covalent acyl-enzyme complex that permanently inactivates the protein (PubMed: 21148555). Because LDTs are absent in humans and critical for the survival of several major human pathogens, they represent a highly specific and valuable target for the development of next-generation antibacterial agents (PubMed: 25691641). Targeting these enzymes is particularly relevant for treating multi-drug resistant tuberculosis and vancomycin-resistant enterococci.

Other names

L,D-transpeptidasePeptidoglycan L,D-transpeptidaseErfK/YbiS/YcfS/YnhG family proteinLdtMt1LdtMt2Ldtfm

Irreversible inhibition through the acylation of the catalytic cysteine residue by carbapenem antibiotics, which prevents the formation of 3-3 peptidoglycan cross-links and leads to cell wall instability (PubMed: 19223571, 21148555).