Directing Drugs to Bugs: Antibiotic-Carbohydrate Conjugates Targeting Biofilm-Associated Lectins of Pseudomonas aeruginosa

Chronic infections by Pseudomonas aeruginosa are characterized by biofilm
formation, which effectively enhances
resistance toward antibiotics. Biofilm-specific antibiotic delivery
could locally increase drug concentration to break antimicrobial resistance
and reduce the drug’s peripheral side effects. Two extracellular P. aeruginosa lectins, LecA and LecB, are essential
structural components for biofilm formation and thus render a possible
anchor for biofilm-targeted drug delivery. The standard-of-care drug
ciprofloxacin suffers from severe systemic side effects and was therefore
chosen for this approach. We synthesized several ciprofloxacin-carbohydrate
conjugates and established a structure–activity relationship.
Conjugation of ciprofloxacin to lectin probes enabled biofilm accumulation in vitro, reduced the antibiotic’s cytotoxicity,
but also reduced its antibiotic activity against planktonic cells
due to a reduced cell permeability and on target activity. This work
defines the starting point for new biofilm/lectin-targeted drugs to
modulate antibiotic properties and ultimately break antimicrobial
resistance.