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

Abstract

Aminoxy analogues of di- and tripeptides in which the peptide linkage is replaced by -CO-NHO-, either as an - or -2-aminoxypropionic acid ( or -OAla) residue, have been examined for antibacterial activity and for uptake into Isolation of analogue-resistant mutants and cross-resistance tests with peptide-transport mutants indicate that all three peptide permeases can transport these backbone-modified analogues. A number of mutants with defects in particular intracellular peptidases show decreased sensitivity to a range of these analogues, 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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1984-09-01
2024-03-28
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