Second lytic target of β‐lactam compounds that have a terminal d‐amino acid residue

Abstract

A new biochemical mechanism of lysing bacterial cells by treatment with certain .beta.-lactam compounds that possess a terminal D-amino acid moiety in their side chain was demonstrated. The two functions of the molecule, the .beta.-lactam and terminal D-amino acid moiety, are both involved in the activity of lysing gram-negative bacteria, which is characterized by very rapid lysis of the cells in the first few hours after their contact with the compound. This mechanism was proved by studies on one such compound, named MT-141, which contains a terminal D-cysteine moiety with free amino and carboxyl groups in the 7.beta.-side chain of the 7.alpha.-methoxy-cephalosporin skeleton. This compound bound to the cell-wall peptidoglycan of Escherichia coli through the D-amino group of its terminal D-amino acid moiety and this seemed to cause rapid cell-lysis. Both activities, of binding to peptidoglycan and of causing rapid cell lysis, were inhibited by certain D-amino acids, but not by L-amino sacids. Mutants were isolated that had simultaneously gained decreased sensitivity to this kind of .beta.-lactam compound and supersensitivity to globomycin, an inhibitor of formation of lipoproteins which function in linking the peptidoglycan to the outer membrane. These results suggest that binding of the terminal D-amino acid moiety of the .beta.-lactam compound to peptidoglycan somehow influences formation of the linkage between the outer membrane and the peptidoglycan and consequently enhances the cell lytic activity of the .beta.-lactam portion of the molecule.