Penicillin-binding protein (Streptococcus pneumoniae) (PBP)

Penicillin-binding proteins (PBPs) in Streptococcus pneumoniae are a group of essential enzymes involved in the final stages of peptidoglycan biosynthesis, which is the primary component of the bacterial cell wall (StatPearls: https://www.ncbi.nlm.nih.gov/books/NBK554404/). S. pneumoniae typically possesses six PBPs, categorized into high-molecular-weight (Class A and Class B) and low-molecular-weight (Class C) proteins, which function as transpeptidases, transglycosylases, and carboxypeptidases to maintain cell wall integrity and shape (PubMed: https://pubmed.ncbi.nlm.nih.gov/10858507/). These proteins are the primary targets for beta-lactam antibiotics, such as penicillins and cephalosporins, which inhibit their enzymatic activity by mimicking the natural D-Ala-D-Ala substrate (UniProt: https://www.uniprot.org/uniprotkb/P0A4G2/entry). In clinical settings, S. pneumoniae is a major human pathogen responsible for pneumonia, meningitis, and sepsis, making PBPs critical therapeutic targets. However, the emergence of penicillin-resistant strains is a significant challenge, often driven by the acquisition of mosaic PBP genes through horizontal gene transfer, which results in proteins with reduced affinity for antibiotics (PubMed: https://pubmed.ncbi.nlm.nih.gov/22431643/). Understanding the structural and functional variations of these proteins is vital for the development of next-generation antimicrobial agents capable of overcoming existing resistance mechanisms. These enzymes are located on the outer surface of the cytoplasmic membrane, making them accessible to circulating antibiotics. The inhibition of these proteins leads to the accumulation of peptidoglycan precursors and triggers autolytic enzymes, resulting in bacterial cell death.

Other names

PBPDD-transpeptidaseDD-carboxypeptidasePeptidoglycan synthaseMurein hydrolasePBP1aPBP1bPBP2aPBP2bPBP2xPBP3

Beta-lactam antibiotics act as structural analogs of the D-alanyl-D-alanine terminus of peptidoglycan precursors, covalently binding to the active site serine of penicillin-binding proteins (StatPearls: https://www.ncbi.nlm.nih.gov/books/NBK554404/). This irreversible inhibition prevents the transpeptidation reaction required for cross-linking peptidoglycan chains, compromising the structural integrity of the bacterial cell wall and ultimately leading to osmotic lysis and cell death (PubMed: https://pubmed.ncbi.nlm.nih.gov/10858507/).