Structure-activity characterization of nitric oxide-releasing dendrimers as dual-action antibacterial agents

The increasing prevalence of antibiotic-resistant bacteria coupled with the inherent resistance of biofilm-based infections have necessitated the development of new antibacterial agents capable of eradicating biofilms without fostering resistance. Nitric oxide (NO), an endogenously produced free radical, holds great promise as an antibacterial agent due to its broad-spectrum antimicrobial action. Combining NO with contact-based biocides on a macromolecular scaffold should further enhance bactericidal action. Herein, the synthesis of NO-releasing antibacterial dendrimers and their anti-biofilm capabilities as a function of exterior modification are described.;Dual-action antibacterial agents were synthesized through the functionalization of poly(amidoamine) dendrimer scaffolds with contact-based biocides and subsequent modification with N-diazeniumdiolate NO donors. Quaternary ammonium- and alkyl chain-modified dendrimers were designed with a range of generations and alkyl chain lengths. Nitric oxide storage was turned so that each set of modified dendrimers exhibited similar NO totals, allowing for the evaluation of antibacterial action independent of NO-release payloads.;The antibacterial action of dual-action dendrimer biocides proved dependent on dendrimer generation, alkyl chain length, and bacterial Gram class. Longer alkyl chain modifications were significantly more bactericidal than both unmodified scaffolds and shorter alkyl chains. Efficacy of the shorter chains was improved with higher dendrimer generations and the addition of NO release. Long alkyl chain dendrimers did not benefit from NO release due to the significant membrane damage they induced precluding intracellular NO buildup. The anti-biofilm action of alkyl chain-modified dendrimers was dependent on the biocide's ability to penetrate into the biofilm and compromise cell membranes, with longer alkyl chains improving biofilm eradication due to greater membrane intercalation. The addition of NO release enhanced the efficacy of dendrimer biocides incapable of good biofilm penetration, indicating the utility of dual-action dendrimers as broad-spectrum anti-biofilm agents.;Electrospun polyurethane fibers capable of delivering NO-releasing dendrimers were fabricated by doping dendrimers into polyurethane solutions prior to electrospinning. The electrospun fiber mats were semi-porous and exhibited sufficient water uptake, demonstrating promise as potential wound dressing materials. Dendrimer- and NO-release rates were tunable by altering the dendrimer modification and polyurethane composition. Nitric oxide-releasing fibers exhibited moderate to high antibacterial activity against planktonic bacteria with minimal cytotoxic effects.