Self-targeting, zwitterionic micellar dispersants enhance antibiotic killing of infectious biofilms-An intravital imaging study in mice.

Abstract

Extracellular polymeric substances (EPS) hold infectious biofilms together and limit antimicrobial penetration and clinical infection control. Here, we present zwitterionic micelles as a previously unexplored, synthetic self-targeting dispersant. First, a pH-responsive poly(ε-caprolactone)-<i>block</i>-poly(quaternary-amino-ester) was synthesized and self-assembled with poly(ethylene glycol)-<i>block</i>-poly(ε-caprolactone) to form zwitterionic, mixed-shell polymeric micelles (ZW-MSPMs). In the acidic environment of staphylococcal biofilms, ZW-MSPMs became positively charged because of conversion of the zwitterionic poly(quaternary-amino-ester) to a cationic lactone ring. This allowed ZW-MSPMs to self-target, penetrate, and accumulate in staphylococcal biofilms in vitro. In vivo biofilm targeting by ZW-MSPMs was confirmed for staphylococcal biofilms grown underneath an implanted abdominal imaging window through direct imaging in living mice. ZW-MSPMs interacted strongly with important EPS components such as eDNA and protein to disperse biofilm and enhance ciprofloxacin efficacy toward remaining biofilm, both in vitro and in vivo. Zwitterionic micellar dispersants may aid infection control and enhance efficacy of existing antibiotics against remaining biofilm.