In Vitro and Murine Efficacy and Toxicity Studies of Nebulized SCC1, a Methylated Caffeine-Silver(I) Complex, for Treatment of Pulmonary Infections

Abstract

The expanding clinical challenge of respiratory tract infections due to resistant bacteria necessitates the development of new forms of therapy. The development of a compound composed of silver coupled to a methylated caffeine carrier (silver carbene complex 1 [SCC1]) that demonstrated in vitro efficacy against bacteria, including drug-resistant organisms, isolated from patients with respiratory tract infections was described previously. The findings of current in vitro studies now suggest that bactericidal concentrations of SCC1 are not toxic to airway epithelial cells in primary culture. Thus, it was hypothesized that SCC1 could be administered by the aerosolized route to concentrate delivery to the lung while minimizing systemic toxicity. In vivo, aerosolized SCC1 delivered to mice resulted in mild aversion behavior, but it was otherwise well tolerated and did not cause lung inflammation following administration over a 5-day period. The therapeutic efficacy of SCC1 compared to that of water was shown in a 3-day prophylaxis protocol, in which mice infected with a clinical strain of Pseudomonas aeruginosa had increased survival, decreased amounts of bacteria in the lung, and a lower prevalence of bacteremia. Similarly, by using an airway infection model in which bacteria were impacted in the airways by agarose beads, the administration of SCC1 was significantly superior to water in decreasing the lung bacterial burden and the levels of bacteremia and markers of airway inflammation. These observations indicate that aerosolized SCC1, a novel antimicrobial agent, warrants further study as a potential therapy for bacterial respiratory tract infections.

Novel symmetrically p-benzyl-substituted 4,5-diaryl-imidazole N-heterocyclic carbene-silver(I) acetate complexes – Synthesis and biological evaluation

“…Youngs et al have reported NHC-silver complexes derived from 4,5-dichloro-1H-imidazole, which show anticancer activity against the human cancer cell lines OVCAR-3 (ovarian), MB157 (breast), and HeLa (cervical) [5]. Furthermore led the synthesis and antimicrobial evaluation of NHC silver complexes derived from 1-benzyl-3-tert-butylimidazole by Ghosh et al to another important contribution [8]. Additionally a larger number of known compounds were evaluated as potential antibiotics by Roland and Jolivalt [9].…”

Preparation and in Vitro Antimicrobial Activity of Silver-Bearing Degradable Polymeric Nanoparticles of Polyphosphoester-block-Poly(l-lactide)

“…designed a library of N -heterocyclic silver carbene complexes (SCCs), which improved the stability of Ag + to light and aqueous solution, allowed for the direct administration of silver-compounds via nebulization, and demonstrated the antimicrobial activity of Ag + against contemporary Gram-positive and Gram-negative pathogens. 16–24 In parallel, Cannon and Youngs et al demonstrated sustained silver release and potent in vitro and in vivo antimicrobial efficacy of SCC10-bearing L-tyrosine polyphosphate nanoparticles (LTP NPs) against the cystic fibrosis pathogen Pseudomonas aeruginosa . 25 Meanwhile, benefiting from polymeric backbone-structured building blocks with precisely controlled architectures, surface characteristics and supramolecular assembly, 26, 27 Cannon, Youngs and Wooley et al highlighted the preparation of smaller particle size and the introduction of functionalities for attachment of targeting moieties by utilizing multifunctional shell cross-linked knedel-like polymeric nanoparticles (SCK NPs) of poly(acrylic acid)- block -polystyrene (PAA- b -PS).…”

N -Heterocyclic Carbene Metal Complexes as Bio-Organometallic Antimicrobial and Anticancer Drugs

“…Several NHC-silver complexes were used in in vivo studies to treat multidrug-resistant pulmonary infections found in cystic fibrosis patients [92], and in vitro and in vivo studies on several strains of cancerous cells [93].…”