Developing a novel chimeric antimicrobial peptide for the treatment of central nervous system bacterial infections

Bacterial meningitis remains a life-threatening central nervous system (CNS) infection with a high mortality rate and long-term neurological sequelae, largely due to the limited ability of most antimicrobials to cross the blood–brain barrier (BBB). Here, we report the rational design of a BBB-targeted chimeric antimicrobial peptide, P-FK5-X-TGN, that combines a palmitoylated random peptide mixture (P-FK5) with the BBB-homing peptide TGN via a flexible hexanoic acid linker (X). The chimeric peptide retained potent antibacterial activity against Neisseria meningitidis (MIC 8 µg/ml) and demonstrated efficient traversal of an in vitro BBB model, reducing bacterial viability better than unconjugated P-FK5 and ciprofloxacin. In a murine model of meningococcal infection, P-FK5-X-TGN was well tolerated and improved survival (67%) compared to P-FK5 (0%) and ciprofloxacin (50%), despite being administered at a 5-fold lower dose. Importantly, treatment with P-FK5-X-TGN also resulted in a ~ 3-log reduction in bacterial burden in the brain. Collectively, these results establish BBB-targeted antimicrobial peptides as an interesting noninvasive strategy for the treatment of CNS infections and highlight P-FK5-X-TGN as a proof-of-concept therapeutic for bacterial meningitis for further studies.