Biological and Medicinal Chemistry

A Study with Peptide Dendrimers Reveals an Extreme pH Dependence of Antibiotic Activity Above pH 7.4

Abstract

The presence of ionizable groups in antimicrobial peptides (AMPs) often induces a pH-dependent activity. Herein we report that removing eight low pKa amino termini in antimicrobial peptide dendrimer (AMPD) G3KL provides dendrimer XC1 with a broader pH-activity range. Furthermore, raising the pH to 8.0 reveals strong activities against Klebsiella pneumoniae and methicillin resistant Staphylococcus aureus (MRSA) against which these AMPDs are inactive at pH 7.4. We observe a similar effect with polymyxin B on MRSA. Binding experiments with a fluorescent AMPD and the effect of high salt concentration suggest that the activity increase reflects stronger electrostatic binding to the bacteria at high pH. pH-profiling of other polycationic antimicrobials (polymers, peptidomimetics, foldamers, dendrimers) might similarly enhance their activity range, with possible use for topical treatments.

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