Combination Effects of Antimicrobial Peptides

Antimicrobial peptides (AMPs) are ancient and conserved across the tree of life. Their efficacy over evolutionary time has been largely attributed to their mechanisms of killing. Yet, the understanding of their pharmacodynamics both in vivo and in vitro is very limited. This is, however, crucial for applications of AMPs as drugs and also informs the understanding of the action of AMPs in natural immune systems. Here, we selected six different AMPs from different organisms to test their individual and combined effects in vitro. We analyzed their pharmacodynamics based on the Hill function and evaluated the interaction of combinations of two and three AMPs. Interactions of AMPs in our study were mostly synergistic, and three-AMP combinations displayed stronger synergism than two-AMP combinations. This suggests synergism to be a common phenomenon in AMP interaction. Additionally, AMPs displayed a sharp increase in killing within a narrow dose range, contrasting with those of antibiotics. We suggest that our results could lead a way toward better evaluation of AMP application in practice and shed some light on the evolutionary consequences of antimicrobial peptide interactions within the immune system of organisms

Bacteria primed by antimicrobial peptides develop tolerance and persist

Funding: ARR and JR were funded by DFG project SFB 973 (C5). RRR and DYB were funded by ETH Zurich (ETH-41 15-2).Antimicrobial peptides (AMPs) are key components of innate immune defenses. Because of the antibiotic crisis, AMPs have also come into focus as new drugs. Here, we explore whether prior exposure to sub-lethal doses of AMPs increases bacterial survival and abets the evolution of resistance. We show that Escherichia coli primed by sub-lethal doses of AMPs develop tolerance and increase persistence by producing curli or colanic acid, responses linked to biofilm formation. We develop a population dynamic model that predicts that priming delays the clearance of infections and fuels the evolution of resistance. The effects we describe should apply to many AMPs and other drugs that target the cell surface. The optimal strategy to tackle tolerant or persistent cells requires high concentrations of AMPs and fast and long-lasting expression. Our findings also offer a new understanding of non-inherited drug resistance as an adaptive response and could lead to measures that slow the evolution of resistance.Peer reviewe

Bacteria primed by antimicrobial peptides develop tolerance and persist

Antimicrobial peptides (AMPs) are key components of innate immune defenses. Because of the antibiotic crisis, AMPs have also come into focus as new drugs. Here, we explore whether prior exposure to sub-lethal doses of AMPs increases bacterial survival and abets the evolution of resistance. We show that Escherichia coli primed by sub-lethal doses of AMPs develop tolerance and increase persistence by producing curli or colanic acid, responses linked to biofilm formation. We develop a population dynamic model that predicts that priming delays the clearance of infections and fuels the evolution of resistance. The effects we describe should apply to many AMPs and other drugs that target the cell surface. The optimal strategy to tackle tolerant or persistent cells requires high concentrations of AMPs and fast and long-lasting expression. Our findings also offer a new understanding of non-inherited drug resistance as an adaptive response and could lead to measures that slow the evolution of resistance

Additional Simulation Results and Pharamacodynamic Concepts from Predicting drug resistance evolution: insights from antimicrobial peptides and antibiotics

Antibiotic resistance constitutes one of the most pressing public health concerns. Antimicrobial peptides (AMPs) of multicellular organisms are considered part of a solution to this problem, and AMPs produced by bacteria such as colistin are last-resort drugs. Importantly, AMPs differ from many antibiotics in their pharmacodynamic characteristics. Here we implement these differences within a theoretical framework to predict the evolution of resistance against AMPs and compare it to antibiotic resistance. Our analysis of resistance evolution finds that pharmacodynamic differences all combine to produce a much lower probability that resistance will evolve against AMPs. The finding can be generalized to all drugs with pharmacodynamics similar to AMPs. Pharmacodynamic concepts are familiar to most practitioners of medical microbiology, and data can be easily obtained for any drug or drug combination. Our theoretical and conceptual framework is, therefore, widely applicable and can help avoid resistance evolution if implemented in antibiotic stewardship schemes or the rational choice of new drug candidates