Chloroalanyl and propargylglycyl dipeptides. Suicide-substrate-containing antibacterials

Abstract

A set of dipeptides containing the amino acid residues .beta.-chloroalanine and propargylglycine, mechanism-based inactivators of purified microbial enzymes (alanine racemase and cystathionine .gamma.-synthase, respectively), were synthesized, their antibacterial properties in vitro were evaluated. Dipeptides containing a single .beta.-chloro-L-alanyl residue or a single L-propargylglycyl residue were potent antibacterials. The in vitro antibiotic activity of .beta.-chloro-L-alanine and of L-propargylglycine was increased as much as 4000-fold by incorporation of these residues into a dipeptide. Compounds that contained only a single enzyme-inactivating amino acid with a 2nd L-alanyl residue had a restricted range of activity: of the species tested, only Streptococcus agalactiae, Staphylococcus aureus and S. epidermidis were sensitivie. Peptides that contained 2 suicide-substrate residues were broad-spectrum antibacterials; as many as 12 spp. of the 16 surveyed were sensitive. Dipeptides that contained an amino-terminal L-methionyl or an L-norvalyl residue and a carboxy-terminal .beta.-chloro-L-alanyl unit were also effective against a large number of organisms. A mixed dipeptide gave apparent synergism of antibiotic action of .beta.-chloro-L-alanine and of L-propargylglycine when these 2 residues were incorporated into a single structure. Peptides of the D,D configuration and ones of L,D stereochemistry were not antibacterials. Peptides containing 1 and 2 D,L-propargylglycyl residues were unresolved sets of diastereomers; the mixtures of compounds were 2-4-fold less active than the correspondingly resolved L,L dipeptides. These findings are consistent with a mechanism of these antibiotics involving stereoselective processing of the peptidyl unit in vivo.