A Study with Peptide Dendrimers Reveals an Extreme pH Dependence of Antibiotic Activity Above pH 7.4
The presence of ionizable groups in antimicrobial peptides (AMPs) often induces a pH-dependent activity. Herein we report that removing eight low p<i>K</i><sub>a</sub> amino termini in antimicrobial peptide dendrimer (AMPD) <b>G3KL</b> provides dendrimer <b>XC1</b> with a broader pH-activity range. Furthermore, raising the pH to 8.0 reveals strong activities against <i>Klebsiella pneumoniae</i> and methicillin resistant <i>Staphylococcus aureus</i> (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.