Chemical characterization and biological properties of NVC-422, a novel, stable N-chlorotaurine analog

Antimicrob Agents Chemother. 2011 Jun;55(6):2688-92. doi: 10.1128/AAC.00158-11. Epub 2011 Mar 21.

Abstract

During oxidative burst, neutrophils selectively generate HOCl to destroy invading microbial pathogens. Excess HOCl reacts with taurine, a semi-essential amino acid, resulting in the formation of the longer-lived biogenerated broad-spectrum antimicrobial agent, N-chlorotaurine (NCT). In the presence of an excess of HOCl or under moderately acidic conditions, NCT can be further chlorinated, or it can disproportionate to produce N,N-dichlorotaurine (NNDCT). In the present study, 2,2-dimethyltaurine was used to prepare a more stable N-chlorotaurine, namely, N,N-dichloro-2,2-dimethyltaurine (NVC-422). In addition, we report on the chemical characterization, in vitro antimicrobial properties, and cytotoxicity of this compound. NVC-422 was shown effectively to kill all 17 microbial strains tested, including antibiotic-resistant Staphylococcus aureus and Enterococcus faecium. The minimum bactericidal concentration of NVC-422 against Gram-negative and Gram-positive bacteria ranged from 0.12 to 4 μg/ml. The minimum fungicidal concentrations against Candida albicans and Candida glabrata were 32 and 16 μg/ml, respectively. NVC-422 has an in vitro cytotoxicity (50% cytotoxicity = 1,440 μg/ml) similar to that of NNDCT. Moreover, our data showed that this agent possesses rapid, pH-dependent antimicrobial activity. At pH 4, NVC-422 completely killed both Escherichia coli and S. aureus within 5 min at a concentration of 32 μg/ml. Finally, the effect of NVC-422 in the treatment of an E. coli-infected granulating wound rat model was evaluated. Treatment of the infected granulating wound with NVC-422 resulted in significant reduction of the bacterial tissue burden and faster wound healing compared to a saline-treated control. These findings suggest that NVC-422 could have potential application as a topical antimicrobial.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Anti-Infective Agents / chemistry
  • Anti-Infective Agents / pharmacology*
  • Cell Line
  • Drug Stability
  • Escherichia coli Infections / drug therapy
  • Hydrogen-Ion Concentration
  • Mice
  • Rats
  • Rats, Sprague-Dawley
  • Taurine / analogs & derivatives*
  • Taurine / chemistry
  • Taurine / pharmacology

Substances

  • Anti-Infective Agents
  • Taurine
  • N-chlorotaurine
  • NVC-422