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

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Abstract
Position 4 analogues of d -alanine in the peptide subunit of uridine 5′-diphosphate- N -acetylmuramyl-Ala 1 - d Glu 2 - Lys 3 - d Ala 4 - d Ala 5 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, d Abu- d Ala, d Nva- d Ala, and d Val- d Ala, only d Nva- d Ala (5 × 10 −4 M) inhibited the growth of Escherichia coli W in the presence of 5 × 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 d Abu- d Ala and d Val- d Ala 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 d Nva- d Ala 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.