Bacterial low-molecular-weight penicillin-binding protein (LMW PBP) (LMW PBP)

Bacterial low-molecular-weight penicillin-binding proteins (LMW PBPs) are a group of enzymes, primarily DD-carboxypeptidases, that play a critical role in the final stages of peptidoglycan synthesis and cell wall remodeling. Unlike high-molecular-weight PBPs which are essential transpeptidases, LMW PBPs typically function to remove the terminal D-alanine residue from pentapeptide side chains, thereby regulating the number of donor stems available for cross-linking and maintaining the structural integrity and shape of the bacterial cell (Moffitt et al., 2007, DOI: 10.1111/j.1365-2958.2007.05719.x). While often non-essential for primary growth in laboratory conditions, they are vital for bacterial fitness, stress response, and the fine-tuning of the cell wall architecture. In the context of infectious diseases, LMW PBPs are significant targets for beta-lactam antibiotics, which mimic the natural D-Ala-D-Ala substrate. Binding of these drugs to the LMW PBPs inhibits their enzymatic activity, leading to alterations in peptidoglycan structure that can sensitize bacteria to other antibiotics or contribute to cell lysis (Typas et al., 2011, DOI: 10.1038/nrmicro2670). Furthermore, LMW PBPs are often involved in antibiotic resistance mechanisms; for instance, their overproduction or modification can sequester beta-lactams or alter the cell wall to reduce drug efficacy. Understanding the specific roles of various LMW PBP isoforms, such as PBP5 and PBP6, remains a key area of research for developing next-generation antibacterial agents that can bypass existing resistance pathways (Nicola et al., 2010, DOI: 10.1021/bi1011519).

Other names

DD-carboxypeptidaseD-alanyl-D-alanine carboxypeptidaseClass C penicillin-binding proteinPBP4PBP5PBP6PBP7DacADacBDacC

Beta-lactam antibiotics act as substrate analogs of the D-Ala-D-Ala terminus of peptidoglycan precursors, covalently binding to the active-site serine of LMW PBPs to form a stable acyl-enzyme intermediate, thereby inhibiting their carboxypeptidase activity and disrupting cell wall homeostasis (Sauvage et al., 2008, DOI: 10.1111/j.1574-6976.2008.00105.x).