Lectin-Targeted Prodrugs Activated by Pseudomonas aeruginosa for Self-Destructive Antibiotic Release

Chronic Pseudomonas aeruginosa infections
are characterized by biofilm formation, a major virulence factor of P. aeruginosa and cause of extensive drug resistance.
Fluoroquinolones are effective antibiotics but are linked to severe
side effects. The two extracellular P. aeruginosa-specific lectins LecA and LecB are key structural biofilm components
and can be exploited for targeted drug delivery. In this work, several
fluoroquinolones were conjugated to lectin probes by cleavable peptide
linkers to yield lectin-targeted prodrugs. Mechanistically, these
conjugates therefore remain non-toxic in the systemic distribution
and will be activated to kill only once they have accumulated at the
infection site. The synthesized prodrugs proved stable in the presence
of host blood plasma and liver metabolism but rapidly released the
antibiotic cargo in the presence of P. aeruginosa in a self-destructive manner in vitro. Furthermore, the prodrugs
showed good absorption, distribution, metabolism, and elimination
(ADME) properties and reduced toxicity in vitro, thus establishing
the first lectin-targeted antibiotic prodrugs against P. aeruginosa.