Transport and Hydrolysis of Antibacterial Peptide Analogues in Escherichia coli: Backbone-modified Aminoxy Peptides

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Abstract
Aminooxy analogs of di- and tripeptides in which the peptide linkage is replaced by -CO-NHO-, either as an L- or D-2-aminooxypropionic acid (L or D-OAla) residue, were examined for antibacterial activity in vitro and for uptake into E. coli. Isolation of analog-resistant mutants and cross-resistance tests with peptide-transport mutants indicate that all 3 peptide permeases can transport these backbone-modified analogs. A number of mutants with defects in particular intracellular peptidases show decreased sensitivity to a range of these analogs, allowing identification of the enzymes responsible for their cleavage and confirming that hydrolysis is essential for their toxicity. Ala-OAla is a bacteriostatic agent that inhibits nucleic acid and protein synthesis within 1 min of being added to an exponentially growing culture. In crude extracts Ala-OAla inhibits transaminase activity but only after liberation of OAla by endogenous peptidases. These antibacterial agents illustrate an approach to drug targeting in which peptide carriers are used to promote uptake of essentially impermeant toxic moieties.

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