Practice question

Peptidoglycan assembly requires synthesis of soluble UDP-N-acetylmuramyl pentapeptide in cytoplasm, attachment to undecaprenyl phosphate carrier to form Lipid II, flipping to external leaflet, polymerization by transglycosylases and final cross-linking of pentapeptide stems by transpeptidases called penicillin-binding proteins possessing active-site serine. The transpeptidase recognizes the terminal D-Ala-D-Ala motif and catalyzes cleavage of the terminal D-alanine with concomitant formation of a new peptide bond between meso-diaminopimelate or lysine and D-alanine from adjacent strand, conferring mechanical rigidity essential to resist turgor. Beta-lactam antibiotics including penicillins, cephalosporins, carbapenems are structural mimics of D-Ala-D-Ala dipeptide geometry. The strained four-membered beta-lactam ring acts as a suicide substrate, rapidly acylating the active-site serine of PBPs and forming a stable, long-lived acyl-enzyme intermediate that is hydrolyzed extremely slowly. Transpeptidation cannot proceed, new cross-links fail to form, and housekeeping autolysins continue to remodel old wall causing net wall degradation. Cells swell, lose shape and lyse, explaining activity preferentially against actively growing cells, Gram-positive susceptibility and resistance via beta-lactamase production or PBP2a expression.