title: Anti-biofilm action of nitric oxide-releasing alkyl-modified poly(amidoamine) dendrimers against Streptococcus mutans.
abstract: The effect of nitric oxide (NO)-releasing dendrimer hydrophobicity on Streptococcus mutans killing and biofilm disruption was examined at pH 7.4 and 6.4, the latter relevant to dental caries. Generation 1 (G1) poly(amidoamine) (PAMAM) dendrimers were modified with alkyl epoxides to generate propyl-, butyl-, hexyl-, octyl-, and dodecyl-functionalized dendrimers. The resulting secondary amines were reacted with NO to form N-diazeniumdiolate NO donor-modified dendrimer scaffolds (total NO ∼1μmol/mg). The bactericidal action of the NO-releasing dendrimers against both planktonic and biofilm-based S. mutans proved greatest with increasing alkyl chain length and at lower pH. Improved bactericidal efficacy at pH 6.4 was attributed to increased scaffold surface charge that enhanced dendrimer-bacteria association and ensuing membrane damage. For shorter alkyl chain (i.e., propyl and butyl) dendrimer modifications, increased antibacterial action at pH 6.4 was due to faster NO-release kinetics from proton-labile N-diazeniumdiolate NO donors. Octyl- and dodecyl-modified PAMAM dendrimers proved most effective for eradicating S. mutans biofilms with NO release mitigating dendrimer scaffold cytotoxicity.
  
  
  CONCLUSIONS
  We report the antibacterial and anti-biofilm efficacy of dual-action nitric oxide (NO)-releasing dendrimers against S. mutans, an etiological agent in dental caries. This work was undertaken to enhance the anti-biofilm action of these scaffolds by employing various alkyl chain modifications. Furthermore, we evaluated the ability of NO to eradicate cariogenic biofilms. We found that at the lower pH associated with dental caries (pH ∼6.4), NO has a more pronounced antibacterial effect for alkyl modifications less capable of biofilm penetration and membrane disruption. Of greatest significance, we introduce dendrimers as a new macromolecular antibacterial agent against the cariogenic bacteria S. mutans.
authors.affiliation: Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Backlund
authors.affiliation: Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.
authors.forename: Brittany V
authors.initials: BV
authors.lastname: Worley
authors.affiliation: Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.
authors.forename: Mark H
authors.initials: MH
authors.lastname: Schoenfisch
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology; D018441:Biofilms / Q000187:drug effects*; D050091:Dendrimers / Q000737:chemistry / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D009569:Nitric Oxide / Q000737:chemistry / Q000494:pharmacology; D011073:Polyamines / Q000737:chemistry / Q000494:pharmacology; D013295:Streptococcus mutans / Q000502:physiology*
chemical_list: D000900:Anti-Bacterial Agents; D050091:Dendrimers; C531249:Poly(amidoamine); D011073:Polyamines; D009569:Nitric Oxide
keywords: Dendrimers; Dental caries; Nitric oxide; Streptococcus mutans