Abstract
Bacterial resistance to drugs is a growing problem, and one that is inspiring a search for new classes of anti-bacterial compounds. This has generated interest in antimicrobial peptides (AMPs), which are key components of innate immune defences. In contrast to conventional antibiotics, however, little is known about how bacteria respond to AMPs, and whether they modify their phenotypic responses based on their prior experiences. Here, we explore whether prior exposure to sublethal doses of AMPs increases bacterial survival and abets the evolution of resistance. We show that Escherichia coli cells primed by sublethal doses of AMPs develop tolerance and generate more persister cells. Priming with the AMPs melittin and pexiganan leads to bacterial production of curli and colanic acid, respectively. Based on the phenotypic data we developed a population dynamic model to show how priming increases persistence and tolerance. The model predicts that priming delays the clearance of infections and fuels the evolution of genetic resistance. Since AMPs are immune effectors our results suggest that the optimal strategy to reduce problems caused by tolerant or persistent cells requires both (a) high concentrations of and (b) fast and long-lasting expression of AMPs. We anticipate that the effects discussed here will apply to many AMPs as well as other drugs that target the cell surface. Our findings also offer a new understanding of phenotypic drug resistance and could lead to measures that slow the evolution of resistance while improving the treatment of persistent infections.