Novel pyochelin-based PEGylated liposomes for enhanced delivery of antibiotics against resistant clinical isolates of Pseudomonas aeruginosa

Abstract

Pseudomonas aeruginosa is a problematic human pathogen resistant to almost all available antibiotics. The important prerequisite for these drugs to target this bacterium is an efficient delivery system. Siderophore-mediated drug delivery system is a promising approach to carry out antibiotics to the cells. Pyochelin, a siderophore of P. aeruginosa, was successfully synthesized in a five-step procedure. PEGylated liposomal pyochelin–antibiotic (L-Pch-Ab) carrier was fabricated by thin-film hydration method. L-Pch-Ab had an average size of 90.31 ± 0.11 nm holding a negative zeta potential at −54.12 ± 0.03 mV (PDI <2). The MIC determined by broth dilution method against three clinical strains isolated from burn wounds showed that L-Pch-Ab significantly reduced (≤16 µg/ml) the MIC values than those of free antibiotics. In the time kill assay, L-Pch-Ab was bactericidal against all strains at most time intervals at 2 × and 4 × MIC up to 24 h. TEM observations revealed that L-Pch-Ab was actively taken up by P. aeruginosa and exhibited membrane deformation within 2 h. Developed L-Pch-Ab fused intimately with the outer membrane of MDRPa and exhibited effective antibacterial activity than free Ab. Furthermore, L-Pch-Ab kills MDRPa within infected HaCaT keratinocytes without any cytotoxic effects at 4× MIC concentrations after 72 h. Thus, the specific targeting of L-Pch-Ab with its higher efficacy to deliver drug by limiting the toxicity will be a novel approach to fight infections caused by P. aeruginosa.