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

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 pK_a amino termini of our reference dendrimer G3KL by substituting the N-terminal lysine residues with aminohexanoic acid provided dendrimer XC1 with a broader pH-activity range. Furthermore, raising the pH to 8.0 revealed strong activities against Klebsiella pneumoniae and methicillin resistant Staphylococcus aureus (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.