Experimental Conditions That Enhance Potency of an Antibacterial Oligo-Acyl-Lysyl

Oligo-acyl-lysyls (OAKs) are synthetic mimics of host defense peptides known to exert antibacterial activity both in cultures and in animal models of disease. Here, we investigated how environmental conditions (temperature, pH, and ionic strength) affect the antibacterial properties of an octamer derivative, C(12)K-7alpha(8). Data obtained with representative bacteria, including the Gram-negative bacterium Escherichia coli and the Gram-positive bacteria Listeria monocytogenes and Staphylococcus aureus, showed that OAK's potency was proportionally affected by pH changes and subsided essentially throughout a wide range of salt concentrations and temperature values, whereas antistaphyloccocal activity was relatively more vulnerable. It was rather the mode of action that was most susceptible to the environmental changes. Thus, OAK's bactericidal effect was limited to a growth-inhibitory effect under acidic pH, low temperatures, or high salt concentrations, whereas basic pH or high temperatures have enhanced the bactericidal kinetics. Properties of binding to model phospholipid membranes provided evidence that correlated the differential modes of action with variable binding affinities. Interestingly, combination of the optimal incubation conditions resulted in a remarkable increase in potency, as expressed by a 16- to 32-fold reduction in the MIC value and by much faster bactericidal rates (>99% death induced within minutes versus hours) compared with the standard incubation conditions. Collectively, the data suggest that OAKs might be useful in developing design strategies for robust antimicrobial peptides that are able to affect a pathogen's viability under a large spectrum of incubation conditions.