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Antimicrob Agents Chemother. 1977 April; 11(4): 638-644
Copyright © 1977 American Society for Microbiology. All Rights Reserved.

Growth Inhibition of Escherichia coli W by D-Norvalyl-D-Alanine: an Analogue of D-Alanine in Position 4 of the Peptide Subunit of Peptidoglycan

¹ Department of Biochemistry and Molecular Biology, Northwestern University, Evanston, Illinois 60201

ABSTRACT

Position 4 analogues of D-alanine in the peptide subunit of uridine 5'-diphosphate-N-acetylmuramyl-Ala¹-DGlu²- Lys³-DAla⁴-DAla⁵ have a significant inhibitory effect on penicillin-sensitive peptidoglycan synthesis in Gaffkya homari (C. V. Carpenter, S. Goyer, and F. C. Neuhaus, 1976). The specificity profile of this in vitro system has been used as a basis for designing analogues with potential antibacterial activity. To circumvent the specificity determinants exerted by D-alanine:D-alanine ligase (adenosine 5'-diphosphate), attention was directed to DD-dipeptides of the type D-alanyl-analogue-D-alanine as a method for incorporating analogues into position 4 of the peptide subunit in vivo. Of the three dipeptides, DAbu-DAla, DNva-DAla, and DVal-DAla, only DNva-DAla (5 x 10^–4 M) inhibited the growth of Escherichia coli W in the presence of 5 x 10^–6 M D-cycloserine. This concentration of D-cycloserine did not inhibit growth, but it potentiated the bactericidal activity of the dipeptide. The lack of antibacterial activity observed with DAbu-DAla and DVal-DAla was correlated with the poor ability of these dipeptides to be taken up via the dipeptide transport system of this organism. Prevention of lysis induced by DNva-DAla plus D-cycloserine by certain dipeptides and not by others supported this correlation. It is proposed that the D-norvalyl residue of the dipeptide is incorporated in vivo into position 4 of the peptide subunit of peptidoglycan, and that this subunit is not an effective substrate in the reaction(s) catalyzed by the penicillin-susceptible enzyme(s) of cross-linked peptidoglycan synthesis.