On the Mechanism of Action of the Antibiotic O -Carbamyl- d -Serine in Streptococcus faecalis

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Abstract
Lynch, Judith L. (Northwestern University, Evanston, Ill.), and Francis C. Neuhaus . On the mechanism of action of the antibiotic O -carbamyl- d -serine in Streptococcus faecalis . J. Bacteriol. 91: 449–460. 1966.—The antibiotic O -carbamyl- d -serine, an analogue of d -alanine, is an inhibitor of bacterial cell-wall biosynthesis. Growth of Streptococcus faecalis R in the presence of O -carbamyl- d -serine resulted in the accumulation of the cell-wall precursor uridine diphosphate-NAc-muramyl- l -alanyl- d -glutamyl- l - lysine (UDP-NAc-muramyl- l -ala- d -glu- l -lys). The incorporation of d -alanine from l -alanine into peptidoglycan is catalyzed by the sequential action of the following enzymes: (i) alanine racemase; (ii) d -alanine: d -alanine ligase [adenosine diphosphate (ADP)]; (iii) UDP-NAc-muramyl- l -ala- d -glu- l -lys: d -ala- d -ala ligase (ADP); (iv) phospho-NAc-muramyl-pentapeptide translocase [uridine monophosphate (UMP)]. O -carbamyl- d -serine is an effective inhibitor of the alanine recemase ( K i = 4.8 × 10 −4 m , K m of l -alanine = 6.8 × 10 −3 m ). In addition, d -ala- O -carbamyl- d -ser was formed when d -alanine and O -carbamyl- d -serine were incubated with d -alanine: d -alanine ligase (ADP). This dipeptide was utilized by the UDP-NAc-muramyl- l -ala- d -glu- l -lys: d -ala- d -ala ligase (ADP) with the formation of UDP-NAc-muramyl- l -ala- d -glu- l -lys- d -ala- O -carbamyl- d -ser. From a consideration of the following results, i.e., (i) accumulation of UDP-NAc-muramyl- l -ala- d -glu- l -lys; (ii) absence of d -ala- O -carbamyl- d -ser accumulation in bacterial cultures grown in the presence of O -carbamyl- d -serine; and (iii) effective inhibition of the racemase, it was concluded that the first enzyme, the racemase, is the primary site of antibiotic action.