Penicillin-binding protein and L,D-transpeptidase (PBP/LDT)

The cell wall of Mycobacterium abscessus is a complex, waxy envelope composed of peptidoglycan, arabinogalactan, and mycolic acids, which provides a formidable barrier to many antibiotics and is essential for bacterial survival (PubMed: 37202409, 36693574). The primary therapeutic targets within this structure are the Penicillin-binding proteins (PBPs) and L,D-transpeptidases (Ldts), which are enzymes that catalyze the final cross-linking steps of peptidoglycan synthesis (PubMed: 35073167, 33177000). M. abscessus is unique among pathogens for its heavy reliance on L,D-transpeptidases to form 3,3-linkages, a feature that contributes to its high level of intrinsic resistance to traditional beta-lactams and necessitates the use of carbapenems like imipenem (mBio: e03529-21, PubMed: 38523311). These enzymes serve as the pharmacological 'receptors' for cell-wall-active drugs, which bind covalently to their active sites to inhibit cell wall biogenesis and induce bacterial lysis (PubMed: 33177000, bioRxiv: 2025.12.15.694292). Additionally, essential regulatory proteins such as the PASTA-domain kinase PknB and the septal transpeptidase PBP-lipo (MAB_0519) coordinate the synthesis and maintenance of the mycobacterial envelope, representing promising targets for novel antimicrobial development (PubMed: 27293150, 35665809). Effectively targeting these cell wall components is critical for managing chronic infections in patients with cystic fibrosis or other structural lung diseases (PubMed: 38523311).

Other names

Mycobacterium abscessus cell wall receptorsD,D-transpeptidaseL,D-transpeptidasePenicillin-binding proteinsLdtsDdtsPBP-lipoMAB_0519Peptidoglycan transpeptidase

Covalent inhibition of transpeptidase activity through binding to the active site of Penicillin-binding proteins (Ddts) and L,D-transpeptidases (Ldts), leading to the disruption of peptidoglycan 4,3 and 3,3 cross-linking and subsequent cell wall destabilization.