Antimicrobial peptide activity is anticorrelated with lipid a leaflet affinity

Abstract

The activity of antimicrobial peptides (AMPs) has significant bacterial species bias, the mechanisms of which are not fully understood. We employed single-molecule tracking to measure the affinity of three different AMPs to hybrid supported bilayers composed of lipid A extracted from four different Gram negative bacteria and observed a strong empirical anticorrelation between the affinity of a particular AMP to a given lipid A layer and the activity of that AMP towards the bacterium from which that lipid A was extracted. This suggested that the species bias of AMP activity is directly related to AMP interactions with bacterial outer membranes, despite the fact that the mechanism of antimicrobial activity occurs at the inner membrane. The trend also suggested that the interactions between AMPs and the outer membrane lipid A (even in the absence of other components, such as lipopolysaccharides) capture effects that are relevant to the minimum inhibitory concentration.

Fig 1. Semi-logarithmic plot of AMP affinity from single-molecule observations of fluorescent AMPs adsorbed on asymmetric hybrid bilayers composed of lipid a isolated from gram-negative bacteria.

The data are plotted vs. the average of previously published MIC values. Table 2 summarizes the sources of the MIC values. The horizonal bars represent the full range of published values. The vertical bars represent the uncertainty in the mean affinity from replicate experiments as described in the main text. The numerical values of these data are tabulated in S1 Table in the Supporting Information.