title: Aggregatibacter actinomycetemcomitans biofilm killing by a targeted ciprofloxacin prodrug.
abstract: A pH-sensitive ciprofloxacin prodrug was synthesized and targeted against biofilms of the periodontal pathogen Aggregatibacter actinomycetemcomitans (Aa). The dose required to reduce the viability of a mature biofilm of Aa by ~80% was in the range of ng cm(-2) of colonized area (mean biofilm density 2.33 × 10(9) cells cm(-2)). A mathematical model was formulated that predicts the temporal change in the concentration of ciprofloxacin in the Aa biofilm as the drug is released and diffuses into the bulk medium. The predictions of the model were consistent with the extent of killing obtained. The results demonstrate the feasibility of the strategy to induce mortality, and together with the mathematical model, provide the basis for design of targeted antimicrobial prodrugs for the topical treatment of oral infections such as periodontitis. The targeted prodrug approach offers the possibility of optimizing the dose of available antimicrobials in order to kill a chosen pathogen while leaving the commensal microbiota relatively undisturbed.
authors: Department of Chemistry & Biochemistry, Montana State University, Bozeman, MT, USA.
authors: Benjamin D
authors: BD
authors: Reeves
authors: Mark
authors: M
authors: Young
authors: Paul A
authors: PA
authors: Grieco
authors: Peter
authors: P
authors: Suci
mesh_terms: D016976:Aggregatibacter actinomycetemcomitans / Q000187:drug effects* / Q000502:physiology*; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D018441:Biofilms / Q000187:drug effects*; D019921:Biotinylation; D002939:Ciprofloxacin / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D018613:Microscopy, Confocal; D008962:Models, Theoretical; D011355:Prodrugs / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D011355:Prodrugs; D002939:Ciprofloxacin
references: J Periodontol. 2002 Oct;73(10):1188-96
references: 12416778
references: Periodontol 2000. 2003;31:32-42
references: 12656994
references: Antimicrob Agents Chemother. 2011 Jul;55(7):3446-52
references: 21518845
references: J Antimicrob Chemother. 2000 Jan;45(1):31-9
references: 10629010
references: Periodontol 2000. 2002;30:40-50
references: 12236894
references: Oral Dis. 2006 Jul;12(4):420-3
references: 16792729
references: Drug News Perspect. 2005 Jul-Aug;18(6):362-74
references: 16247514
references: J Periodontal Res. 2009 Aug;44(4):443-51
references: 18973535
references: J Periodontol. 2000 Sep;71(9):1448-52
references: 11022774
references: J Clin Periodontol. 2002 Aug;29(8):736-42
references: 12390570
references: Arch Oral Biol. 2011 Oct;56(10):1055-63
references: 21507381
references: Microbes Infect. 2005 Apr;7(4):738-47
references: 15850760
references: Org Biomol Chem. 2011 Dec 21;9(24):8288-300
references: 22052022
references: Mol Oral Microbiol. 2010 Aug;25(4):275-92
references: 20618701
references: Infect Immun. 2009 Sep;77(9):3542-51
references: 19564387
references: J Am Dent Assoc. 2004 Dec;135(12):1728-32
references: 15646608
references: Bioconjug Chem. 1990 Nov-Dec;1(6):431-7
references: 2099189
references: Antimicrob Agents Chemother. 2011 Nov;55(11):5205-13
references: 21844316
references: Antimicrob Agents Chemother. 2010 Jun;54(6):2489-96
references: 20385858
references: Int J Antimicrob Agents. 1998 Feb;9(4):239-53
references: 9573494
references: Antimicrob Agents Chemother. 2006 Nov;50(11):3651-7
references: 17060534
references: Antimicrob Agents Chemother. 1997 Jun;41(6):1352-8
references: 9174198
references: Antimicrob Agents Chemother. 2011 Jun;55(6):2679-87
references: 21402858
references: Toxicol Sci. 2010 Feb;113(2):315-25
references: 19920072
references: Antimicrob Agents Chemother. 2005 Mar;49(3):1184-9
references: 15728923
references: Eur J Pharm Biopharm. 2000 Jul;50(1):83-99
references: 10840194
references: Nat Biotechnol. 2003 Dec;21(12):1480-5
references: 14625561
references: J Clin Periodontol. 2008 Feb;35(2):89-105
references: 18199146
references: J Bacteriol. 2003 Aug;185(16):4693-8
references: 12896987
references: Clin Exp Immunol. 2007 Jan;147(1):128-38
references: 17177972
references: Proc Natl Acad Sci U S A. 2003 Jun 10;100(12):7295-300
references: 12756291
references: J Med Chem. 2001 Jun 21;44(13):2139-51
references: 11405651
references: J Clin Microbiol. 2007 Dec;45(12):3859-69
references: 17942658
references: Appl Environ Microbiol. 2003 Mar;69(3):1702-9
references: 12620862