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. Author summary Animals and plants defend themselves with ancient molecules called antimicrobial peptides (AMPs) against pathogen. As more and more bacterial diseases have become drug resistant, these AMPs are considered as promising alternatives. In natural situation such as on the skin, bacteria are often exposed to low concentrations of AMPs that do no kill. Here we show that the bacterium Escherichia coli when exposed to such low concentrations becomes recalcitrant to killing concentrations of the same AMPs. We report the ways in which the bacteria alter their surface to do so. We then use a mathematical model to show that these effects caused by low concentrations can drive the evolution of resistance. From the perspective of an organism using AMPs in self-defense, the best option is to deploy high concentrations of AMPs for long. Our findings also offer a new understanding of similar drug resistance mechanisms.

Automated summary

Antimicrobial peptides are important components of innate immunity and potential new drugs to combat antibiotic resistance. Exposure to sub-lethal doses of AMPs can increase bacterial tolerance and persistence, leading to the evolution of resistance. High concentrations of AMPs and sustained expression are necessary to effectively target tolerant or persistent cells.