The increasing prevalence of antibiotic-resistant bacteria in clinical settings has led to biofilm-based infections that display a pronounced resistance to antibiotics, necessitating the development of new, more effective therapeutics.  Combining two mechanistically different antibacterial agents (e.g., non-depleting biocide with releasable agent) on a single scaffold represents a promising strategy for increasing bactericidal efficacy while offsetting the development of resistance.  Herein, we describe the synthesis of alkyl chain-modified dendrimers as contact-based biocides by tethering epoxides of varying alkyl chain length (i.e, butyl, hexyl, octyl, and dodecyl) to the dendrimer exterior.  The dendrimers are further modified with N-diazeniumdiolate NO donors to yield NO-releasing dual-action dendrimer biocides.  We evaluate the efficacy of these dendrimer biocides against Pseudomonas aeruginosa, Staphylococcus aureus, and methicillin-resistant Staphylococcus aureus biofilms as a function of alkyl chain length and dendrimer generation.  Fluorescent confocal microscopy is used to visualize dendrimer-bacteria association, intracellular NO accumulation, and bacterial cell death.  These studies demonstrate the potential to tune macromolecular scaffolds for optimal biofilm eradication.

Nitric oxide-releasing dual-action dendrimer biocides for biofilm eradication

248th National Meeting (2014)

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