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

Abstract

In our efforts to develop peptide dendrimers as a new class of antimicrobial peptides (AMPs) against Gram-negative bacteria, we investigated their activity at acidic and basic pH, which correspond to the conditions of the site of bacterial infections on skin or biofilms and chronic wounds respectively. Removing the eight low p<i>K</i><sub>a</sub> amino termini of our reference dendrimer <b>G3KL</b> by substituting the<i> N</i>-terminal lysine residues with aminohexanoic acid provided dendrimer <b>XC1</b> with a broader pH-activity range. Furthermore, raising the pH to 8.0 revealed strong activities against <i>Klebsiella pneumoniae</i> and methicillin resistant <i>Staphylococcus aureus</i> (MRSA) against which the dendrimers are inactive at pH 7.4, an effect which we also observed with polymyxin B and tentatively assign to stronger binding to the bacteria at higher pH as observed with a fluorescence labeled dendrimer analog.