Abstract
N-chlorotaurine (NCT), the main representative of long-lived oxidants produced by granulocytes and monocytes, is known to exert broad-spectrum microbicidal activity. Here we show that NCT directly inactivates Shiga toxin 2 (Stx2), used as a model toxin secreted by enterohemorrhagic Escherichia coli (EHEC). Bacterial growth and Stx2 production were both inhibited by 2 mM NCT. The cytotoxic effect of Stx2 on Vero cells was removed by ≥5.5 mM NCT. Confocal microscopy and FACS analyses showed that the binding of Stx2 to human kidney glomerular endothelial cells was inhibited, and no NCT-treated Stx2 entered the cytosol. Mass spectrometry displayed oxidation of thio groups and aromatic amino acids of Stx2 by NCT. Therefore, long-lived oxidants may act as powerful tools of innate immunity against soluble virulence factors of pathogens. Moreover, inactivation of virulence factors may contribute to therapeutic success of NCT and novel analogs, which are in development as topical antiinfectives.
Highlights
N-chlorotaurine (Cl-HN-CH2-CH2-SO3H, NCT), an N-chloro derivate of the amino acid taurine, is a long lived oxidant produced in high amounts by stimulated human granulocytes and monocytes [1,2,3]
The finding that mainly NCT, and other chloramines are produced by leukocytes as long-lived oxidants with antiinflammatory and antimicrobial properties, implicated their importance for the human defense system [1,4,5,30]
Rapid loss of virulence of pathogens and first studies on inactivation or downregulation of the virulence factors gliotoxin and aspartyl proteinases in the presence of NCT [9,17,18,19] prompted us to investigate in detail the impact of this substance against a model toxin
Summary
N-chlorotaurine (Cl-HN-CH2-CH2-SO3H, NCT), an N-chloro derivate of the amino acid taurine, is a long lived oxidant produced in high amounts by stimulated human granulocytes and monocytes [1,2,3]. One major advantage is the very good tolerability as a mild endogenous active chlorine compound, so that sensitive body regions and cavities can be irrigated [12]. These findings encouraged the development of analog chloramines with even higher solution stability, Nmonochloro-dimethyltaurine (Cl-HN-CH2-(CH3)2-CH2-SO3-Na, NVC-612) and N,N-dichloro-dimethyltaurine (Cl2-N-CH2(CH3)2-CH2-SO3-Na, NVC-422), which are promising new antiinfective agents [13,14,15]
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