title: Chemical characterization and biological properties of NVC-422, a novel, stable N-chlorotaurine analog.
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.
authors.affiliation: NovaBay Pharmaceuticals, 5980 Horton Street, Suite 550, Emeryville, CA 94608, USA. lwang@novabaypharma.com
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.forename: Barbara
authors.initials: B
authors.lastname: Belisle
authors.forename: Mansour
authors.initials: M
authors.lastname: Bassiri
authors.forename: Ping
authors.initials: P
authors.lastname: Xu
authors.forename: Dmitri
authors.initials: D
authors.lastname: Debabov
authors.forename: Chris
authors.initials: C
authors.lastname: Celeri
authors.forename: Nichole
authors.initials: N
authors.lastname: Alvarez
authors.forename: Martin C
authors.initials: MC
authors.lastname: Robson
authors.forename: Wyatt G
authors.initials: WG
authors.lastname: Payne
authors.forename: Ramin
authors.initials: R
authors.lastname: Najafi
authors.forename: Behzad
authors.initials: B
authors.lastname: Khosrovi
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D004355:Drug Stability; D004927:Escherichia coli Infections / Q000188:drug therapy; D006863:Hydrogen-Ion Concentration; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D013654:Taurine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000890:Anti-Infective Agents; D013654:Taurine; C043410:N-chlorotaurine; C560851:NVC-422