Penicillinbinding

Penicillin binding refers to the specific interaction between β‑lactam antibiotics, such as penicillins, and bacterial enzymes known as penicillin‑binding proteins (PBPs). PBPs are a diverse group of membrane‑associated enzymes that catalyze the final stages of peptidoglycan synthesis, including transglycosylation and transpeptidation, which are essential for cell‑wall integrity and bacterial survival. The β‑lactam ring of penicillins mimics the D‑alanine‑D‑alanine moiety of the peptidoglycan substrate, allowing the drug to acylate the active‑site serine of PBPs in a covalent, irreversible manner. This acylation blocks the enzymes’ catalytic activity, leading to defective cell‑wall cross‑linking, osmotic instability, and ultimately bacterial lysis.

Different bacterial species possess multiple PBPs with varying affinities for penicillins, contributing to the spectrum of activity of each β‑lactam drug. In Gram‑positive organisms, high‑affinity PBPs are often the primary targets, whereas Gram‑negative bacteria may require penetration of the outer membrane and may be affected by lower‑affinity PBPs. Mutations in PBP genes or acquisition of alternative PBPs with reduced penicillin affinity constitute common mechanisms of β‑lactam resistance, exemplified by methicillin‑resistant Staphylococcus aureus (MRSA) which expresses PBP2a.

The study of penicillin binding has informed the design of newer β‑lactams and β‑lactamase inhibitors, aiming to improve binding potency, broaden antimicrobial spectra, and overcome resistance mechanisms. Quantitative assessment of penicillin binding, typically using radiolabeled or fluorescent penicillins, remains a standard tool in microbiological research and clinical diagnostics.