Antibacterial Activity and Uptake into Escherichia coli of Backbone-modified Analogues of Small Peptides

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Abstract
Analogs of di- and tripeptides in which the peptide backbone is modified were examined for antibacterial activity in vitro and for uptake into E. coli. Aminoxy and hydrazino types, in which the peptide linkage is replaced, respectively, by -CO-NHO- or -CO-NH-NH-, were active against E. coli, Staphylococcus aureus and Salmonella dublin; retro, .alpha.-aza, tetrazole and hydroxamic types were inactive. Highest potency against all 3 spp. was found in aminoxy analog containing D-2-aminoxypropionic acid (D-OAla) residues, Ala-D-OAla being active at < 1 mg. Uptake into E. coli was seen with all active types, but, with the exception of hydroxamic analogs, not with the inactive types. Following uptake the toxic analogs were rapidly hydrolyzed; the constituent amino acid residues underwent exodus. The substrate specificities of the peptide transport systems were further defined on the basis of the results.