An antibiofilm coating of 5‐aryl‐2‐aminoimidazole covalently attached to a titanium surface

Abstract

Biofilms, especially those formed by Staphylococcus aureus, play a key role in the development of orthopedic implant infections. Eradication of these infections is challenging due to the elevated tolerance of biofilm cells against antimicrobial agents. In this study, we developed an antibiofilm coating consisting of 5-(4-bromophenyl)-N-cyclopentyl-1-octyl-1H-imidazol-2-amine, designated as LC0024, covalently bound to a titanium implant surface (LC0024-Ti). We showed in vitro that the LC0024-Ti surface reduces biofilm formation of S. aureus in a specific manner without reducing the planktonic cells above the biofilm, as evaluated by plate counting and fluorescence microscopy. The advantage of compounds that only inhibit biofilm formation without affecting the viability of the planktonic cells, is that reduced development of bacterial resistance is expected. To determine the antibiofilm activity of LC0024-Ti surfaces in vivo, a biomaterial-associated murine infection model was used. The results indicated a significant reduction in S. aureus biofilm formation (up to 96%) on the LC0024-Ti substrates compared to pristine titanium controls. Additionally, we found that the LC0024-Ti substrates did not affect the attachment and proliferation of human cells involved in osseointegration and bone repair. In summary, our results emphasize the clinical potential of covalent coatings of LC0024 on titanium implant surfaces to reduce the risk of orthopedic implant infections.

Inhibiting bacterial cooperation is an evolutionarily robust anti-biofilm strategy

“…For example, an inhibitor might be given prophylactically to inhibit Salmonella colonization in the gut when the risk of exposure to Salmonella is high, as is currently done with probiotics 72 and vaccines 73 . The potential for clinical application is further supported by our recent reports showing that 2-aminoimidazoles can inhibit biofilm formation in vivo in a subcutaneous model in rats 14 , have low cytotoxicity against different mammalian cell types (tumor cell lines and bone cells 35,74 ) and do not affect the survival of Caenorhabditis elegans, a small nematode that is widely used for toxicity testing and is considered to have high predictive value for toxicity in mammals 75 . However, while clinical potential clearly exists, the assays we report here are most reflective of industrial treatments.…”

“…We have previously reported that 5-aryl-2-aminoimidazoles prevent EPS production of S. Typhimurium by reducing the transcription of csgD and its regulon 36 . These compounds can be coated to surfaces-both covalently 14 or in a slow-release matrix 71 to prevent Salmonella biofilm formation in the food industry. Such inhibitors also have clinical potential.…”

“…Several approaches have been proposed ranging from blocking bacterial attachment, to inhibiting or destabilizing EPS, and interfering with quorum sensing [11][12][13] . Given the limited permeability of established biofilms, particular promise comes from strategies that continually treat surfaces to prevent the formation of biofilms 14 .…”

“…We, therefore, sought to design a treatment strategy that inhibited biofilm and, critically, where we can demonstrate that resistant strains are counter selected. Our approach centers upon in-house developed 5-aryl-2-aminoimidazole-based inhibitors 14,[33][34][35][36] of EPS production in Salmonella biofilms. Salmonella species form biofilms outside and inside the host and EPS both helps cells attach and protects against eradication by mechanical cleaning, disinfectants, antibiotics and the host immune system 37 .…”

Biodistribution, biocompatibility and targeted accumulation of magnetic nanoporous silica nanoparticles as drug carrier in orthopedics

“…Apart from intensive costs, this leads to high burdens for the patient as well as risks like amputation of the affected limb or even death in case of treatment failure [5,17]. So far, different prevention methods were studied avoiding bacterial adhesion in combination with enhancing osseointegration [18,19] like surface modifications or antimicrobial coatings of implants [20][21][22][23].…”