Differences in Relevant Physicochemical Properties Correlate with Synergistic Activity of Antimicrobial Peptides

Abstract

AbstractWith the urgent need for new medical approaches due to increased bacterial resistance to antibiotics, antimicrobial peptides (AMPs) have been considered as potential treatments for infections. Experiments indicate that combinations of several types of AMPs might be more effective at inhibiting bacterial growth with reduced toxicity and a lower likelihood of inducing bacteria resistance. The molecular mechanisms of AMP-AMP synergistic antimicrobial activity, however, remain not well understood. Here, we present a theoretical approach that allows us to relate the physicochemical properties of AMPs and their antimicrobial cooperativity. A concept of physicochemical similarity is introduced, and it is found that less similar AMPs with respect to certain physicochemical properties lead to greater synergy because of their complementary antibacterial actions. The analysis of correlations between the similarity and the antimicrobial properties allows us to effectively separate synergistic from non-synergistic AMPs pairs. Our theoretical approach can be used for the rational design of more effective AMPs combinations for specific bacterial targets, for clarifying the mechanisms of bacterial elimination, and for a better understanding of cooperativity phenomena in biological systems.Author summaryIt is impossible to imagine modern medicine without antibiotics. But there is a growing problem of increased bacterial resistance to them. These considerations stimulated a search for novel methods to defend against infections. Antimicrobial peptides (AMPs) came out as powerful antibacterial agents. It was also found that combinations of AMPs are even more efficient than individual peptides. The mechanisms of such synergistic activities, however, are not understood. We developed a computational framework that allows us to connect the physicochemical properties of AMPs and their abilities to cooperatively eliminate infections. It is found that less similar peptides might exhibit synergy because of their complementary antibacterial properties. Our theoretical approach might lead to a better rational design of new antimicrobial drugs.