Bifunctional Coating with Sustained Release of 4-Amide-piperidine-C12 for Long-Term Prevention of Bacterial...

Bacterial colonization by nosocomial pathogens on medical device surface can cause serious and life-threatening infections. We showed that 4-amide-piperidine-C12 (4AP12), the base form of 4-dodecaneamidepiperidine HCl, has broad-spectrum antimicrobial activity against both Gram-negative and Gram-positive bacteria and fungi. Resistance assay confirmed that prolonged exposure of bacteria to subinhibitory concentrations of 4AP12 did not induce resistance to 4AP12. The possible antimicrobial mechanism of 4AP12 was investigated, and attributed to the disruption of the cell membrane of microorganisms and subsequent cell lysis. The hydrophobic 4AP12 was incorporated in Pluronic F127 diacrylate (F127DA) micelles, which were then graft-copolymerized with acrylic acid and cross-linked onto ozonized silicone surface. Sulfobetaine methacrylate and F127DA were then graft-copolymerized as an antifouling layer on top of the F127DA-AA hydrogel containing the 4AP12, thus forming a microscale two-layer bifunctional coating. Sustained release of 4AP12 at a rate of up to 1 μg/day per cm² of hydrogel-coated silicone surface was achieved and this was sufficient to inhibit ∼97% of bacterial colonization by Acinetobacter baumannii in artificial urine medium under static condition over a 14-day period. Bacterial colonization by Escherichia coli and Pseudomonas aeruginosa under similar conditions was also significantly reduced. In addition, after 96 h exposure to flowing artificial urine (0.7 mL/min), Escherichia coli colonization on the 4AP12-loaded hydrogel-coated surface was reduced by ∼89% compared to the pristine surface. The concentration of 4AP12 that was released and was effective in inhibiting bacterial colonization did not result in significant cytotoxicity to human epithelial cells.