Lactams, reaction with enzymes, hydroxylation

The antibiotic activity of certain (3-lactams depends largely on their interaction with two different groups of bacterial enzymes. (3-Lactams, like the penicillins and cephalosporins, inhibit the DD-peptidases/transpeptidases that are responsible for the final step of bacterial cell wall biosynthesis.63 Unfortunately, they are themselves destroyed by the [3-lactamases,64 which thereby provide much of the resistance to these antibiotics. Class A, C, and D [3-lactamases and DD-peptidases all have a conserved serine residue in the active site whose hydroxyl group is the primary nucleophile that attacks the substrate carbonyl. Catalysis in both cases involves a double-displacement reaction with the transient formation of an acyl-enzyme intermediate. The major distinction between [3-lactamases and their evolutionary parents the DD-peptidase residues is the lifetime of the acyl-enzyme it is short in (3-lactamases and long in the DD-peptidases.65-67... 

These /3-lactam antibiotics apparently work by interfering with the synthesis of bacterial cell walls. Figure 21-11 shows how the carbonyl group of the /3-lactam acy-lates a hydroxyl group (from a serine residue) on one of the enzymes involved in making the cell wall. The acylated enzyme is inactive for synthesis of the cell wall protein. This acylation step is unusual because it converts an amide to an ester, an uphill reaction that we would assume to be endothermic. With this /3-lactam, however, the strain of the four-membered ring activates the amide enough for it to acylate an alcohol to form an ester in an exothermic step. 

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