Peptidoglycan transpeptidase bacterial

Extensive investigations of the properties of PBPs of E. coli, strain K12, were carried out. The results are indicative of our present understanding of PBPs and will be outlined. It should be stated that it is now understood that penicillin-sensitive enzymes such as DD-Cbase, peptidoglycan transpeptidase, and endopeptidases identified earlier are almost certainly identical with the PBPs under discussion here. Multiple PBPs have been discovered in all bacterial membranes studied. It is also now apparent that the interactions of (3-lactam antibiotics with bacteria can result in one or more effects on the physiology and structure of the cell. Thus inhibition of cell division can be observed so can lysis, bulge formation, or even the development of ovoid cell forms stable to osmosis. 

A variety of enzymatic mechanisms for antibiotic resistance are known. Hydrolysis of the lactam rings of /3-lactams, cephalosporins, and carbapenams destroys their ability to inhibit transpeptidases that cross-link peptidoglycan in bacterial cell walls. Modification of aminoglycoside antibiotics by acetylation, phosphorylation, or adenylation interferes with their ability to bind to the 16S subunit of the ribosome. Streptogramin activity can be destroyed by acetylation or by an elimination reaction that opens the lactone ring. The enzymes responsible for these detoxification reactions evolved in response to naturally occurring antibiotics, but are easily adapted to modify semisynthetic and completely synthetic antibiotics. For example, only a few point mutations are needed to enhance the ability of TEM /3-lactamases to hydrolyze third-generation cephalosporins such as cefotaxime and ceftazidime. ... 

Transpeptidases Bacterial enzymes involved in the cross-linking of linear peptidoglycan chains, the final step in cell wall synthesis... 

The (3-lactam antibiotics structurally resemble the terminal D-alanyl-D-alanine (o-Ala-o-Ala) in the pen-tapeptides on peptidoglycan (murein) (Fig. 45.1). Bacterial transpeptidases covalently bind the (3-lactam antibiotics at the enzyme active site, and the resultant acyl enzyme molecule is stable and inactive. The intact (3-lactam ring is required for antibiotic action. The (3-lactam ring modifies the active serine site on transpeptidases and blocks further enzyme function. 

Beta-lactam penicillins prevent the biosynthesis of a dipeptidoglycan which forms the peptidoglycan cell wall in bacteria. This results in cell death and bactericidal activity. Specifically, they acylate a specific bacterial D-transpeptidase, which inactivates this enzyme and it therefore cannot form peptide crosslinks of two linear peptidoglycan strands for cell wall formation. 

Figure 2 Mode of action of the prototypical lantibiotic nisin. (a) The peptidoglycan precursor lipid II is composed of an N-acetylglucosamine-p-1,4-N-acetylmuramic acid disaccharide (GIcNAc-MurNAc) that is attached to a membrane anchor of 11 isoprene units via a pyrophosphate moiety. A pentapeptide is linked to the muramic acid. Transglycosylase and transpeptidase enzymes polymerize multiple lipid II molecules and crosslink their pentapeptide groups, respectively, to generate the peptidoglycan. (b) The NMR solution structure of the 1 1 complex of nisin and a lipid II derivative in DMSO (6). (c) The amino-terminus of nisin binds the pyrophosphate of lipid II, whereas the carboxy-terminus inserts into the bacterial membrane. Four lipid II and eight nisin molecules compose a stable pore, although the arrangement of the molecules within each pore is unknown (5).

Figure 6.8 Pendllins are similar to the bacterial peptidoglycan terminal alanylalanine moiety. Because of this similarity, the enzyme transpeptidase recognizes p-lactam antibiotics as substrate. As a result of this the p-lactam is Incorporated in the peptide chain thereby making peptide-peptide cross-iinking impossible. The occurrence of this phenomenon stops the construction of the bacterial cell wall.

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