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The β-lactam ring is a structure common to all β-lactam antibiotics. Presence of the protein penicillin binding protein 2A (PBP2A) is responsible for the antibiotic resistance seen in methicillin-resistant Staphylococcus aureus (MRSA).
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Research on PBPs has led to the discovery of new semi-synthetic β-lactams, wherein altering the side-chains on the original penicillin molecule has increased the affinity of PBPs for penicillin, and, thus, increased effectiveness in bacteria with developing resistance. These experiments change the structure of PBP by adding different amino acids into the protein, allowing for new discovery of how the drug interacts with the protein. Resistance to antibiotics has come about through overproduction of PBPs and formation of PBPs that have low affinity for penicillins (among other mechanisms such as lactamase production). Bacterial cell wall synthesis and the role of PBPs in its synthesis is a very good target for drugs of selective toxicity because the metabolic pathways and enzymes are unique to bacteria. There has been a great deal of research into PBPs because of their role in antibiotics and resistance. This is an irreversible reaction and inactivates the enzyme. When they bind to penicillin, the β-lactam amide bond is ruptured to form a covalent bond with the catalytic serine residue at the PBPs active site. PBPs bind to β-lactam antibiotics because they are similar in chemical structure to the modular pieces that form the peptidoglycan. In contrast, high-molecular-weight PBPs are independent from MreB and maintain cell wall integrity by detecting and repairing defects in the peptidoglycan. Some low-molecular-weight PBPs associate with the MreB cytoskeleton and follow its rotation around the cell, inserting petipdoglycan in an oriented manner during cell growth. The enzyme has a penicillin-insensitive transglycosylase N-terminal domain (involved in formation of linear glycan strands) and a penicillin-sensitive transpeptidase C-terminal domain (involved in cross-linking of the peptide subunits) and the serine at the active site is conserved in all members of the PBP family. In all bacteria that have been studied, enzymes have been shown to catalyze more than one of the above reactions. Purified enzymes have been shown to catalyze the following reactions: D-alanine carboxypeptidase, peptidoglycan transpeptidase, and peptidoglycan endopeptidase. PBPs have been shown to catalyze a number of reactions involved in the process of synthesizing cross-linked peptidoglycan from lipid intermediates and mediating the removal of D- alanine from the precursor of peptidoglycan. Inhibition of PBPs leads to defects in cell wall structure and irregularities in cell shape, for example filamentation, pseudomulticellular forms, lesions leading to spheroplast formation, and eventual cell death and lysis. Bacterial cell wall synthesis is essential to growth, cell division (thus reproduction) and maintaining the cellular structure in bacteria. PBPs are all involved in the final stages of the synthesis of peptidoglycan, which is the major component of bacterial cell walls. Proteins that have evolved from PBPs occur in many higher organisms and include the mammalian LACTB protein. The PBPs are usually broadly classified into high-molecular-weight (HMW) and low-molecular-weight (LMW) categories. The different PBPs occur in different numbers per cell and have varied affinities for penicillin. coli ranging in molecular weight from 40,000 to 91,000. For example, Spratt (1977) reports that six different PBPs are routinely detected in all strains of E. There are a large number of PBPs, usually several in each organism, and they are found as both membrane-bound and cytoplasmic proteins.