PaAP-Activatable NIR Probe for Diagnosing, Imaging, and Discovering Small-Molecule Therapeutics against Implant-Associated Biofilm Infections

Biofilm
formation on medical implants causes implant-associated
infections (IAIs), leading to high morbidity and mortality. Developing
molecular tools for precise biofilm detection, along with novel strategies
and agents to target biofilm-related IAIs, is crucial for improving
treatment options and patient outcomes. Pseudomonas
aeruginosa aminopeptidase (PaAP), a key biofilm-associated
virulence factor, is a promising target for combating infections.
Here, we developed a PaAP-activatable near-infrared (NIR) fluorescent
probe, Hcy-NEO-Leu, for real-time, specific, and sensitive
detection of PaAP activity. This probe enables noninvasive imaging
of the P. aeruginosa biofilm in vitro
and in vivo. The probe also identified LY-58, a lycorine
derivative that disrupts biofilm formation without affecting bacterial
growth or mammalian cell viability, enhancing tobramycin penetration
and overcoming antibiotic resistance. This study introduces LY-58 as a promising adjunctive therapy. In conclusion, the
PaAP-activatable NIR imaging probe, combined with LY-58, offers innovative tools for the early diagnosis and effective treatment
of IAIs.