Antibiotic resistance is a growing public health crisis. To address the development of bacterial resistance, the use of antibiotics has to be minimized for nonsystemic applications in humans, as well as in animals and plants. Possible substitutes with low potential for developing resistance are active chlorine compounds that have been in clinical use for over 180 years. These agents are characterized by pronounced differences in their chlorinating and/or oxidizing activity, with hypochlorous acid (HOCl) as the strongest and organic chloramines as the weakest members. Bacterial killing in clinical practice is often associated with unwanted side effects such as chlorine consumption, tissue irritation, and pain, increasing proportionally with the chlorinating/oxidizing potency. Since the chloramines are able to effectively kill pathogens (bacteria, fungi, viruses, protozoa), their application as anti-infectives is advisable, all the more so as they exhibit additional beneficial properties such as destruction of toxins, degradation of biofilms, and anticoagulative and anti-inflammatory activities. Within the ample field of chloramines, the stable N-chloro derivatives of ?-aminosulfonic acids are most therapeutically advanced. Being available as sodium salts, they distinguish themselves by good solubility and absence of smell. Important representatives are N-chlorotaurine, a natural compound occurring in the human immune system, and novel mono- and dichloro derivatives of dimethyltaurine, which feature improved stability.
Trichomoniasis, caused by the protozoan Trichomonas vaginalis, is usually treated with metronidazole, however resistance is on the rise. In this study, N-chlorotaurine (NCT), a new endogenous mild active chlorine compound for topical use, killed T. vaginalis in vitro within 15 min of treatment at a concentration of 55 mM (1%), which is well tolerated by human tissue. The activity of NCT was further enhanced by addition of ammonium chloride (NH(4)Cl). A combination of 5.5 mM (0.1%) NCT plus 19 mM (0.1%) NH(4)Cl killed 100% of trichomonads within 5 min.
N-chlorotaurine, the N-chloro derivative of the amino acid taurine, is a long-lived oxidant produced by activated human granulocytes and monocytes. Supported by a high number of in vitro studies, it has mainly anti-inflammatory properties and seems to be involved in the termination of inflammation. The successful synthesis of the crystalline sodium salt (Cl-HN-CH(2)-CH(2)-SO(3)Na, NCT) facilitated its development as an endogenous antiseptic. NCT can be stored long-term at low temperatures, and it has killing activity against bacteria, fungi, viruses and parasites. Transfer of the active chlorine to amino groups of molecules of both the pathogens and the human body (transhalogenation) enhances rather than decreases its activity, mainly because of the formation of monochloramine. Furthermore, surface chlorination after sublethal incubation times in NCT leads to a post-antibiotic effect and loss of virulence of pathogens, as demonstrated for bacteria and yeasts. Being a mild oxidant, NCT proved to be very well tolerated by human tissue in Phase I and II clinical studies. A 1% aqueous solution can be applied to the eye, skin ulcerations, outer ear canal, nasal and paranasal sinuses, oral cavity and urinary bladder, and can probably be used for inhalation. Therapeutic efficacy in Phase II studies has been shown in external otitis, purulently coated crural ulcerations and keratoconjunctivitis, so far. Based upon all presently available data, NCT seems to be an antiseptic with a very good relation between tolerability and activity. Recently, C-methylated derivatives of NCT have been invented, which are of interest because of improved stability at room temperature.
N-chlorotaurine, a long-lived oxidant produced by human leukocytes, can be applied in human medicine as an endogenous antiseptic. Its antimicrobial activity can be enhanced by ammonium chloride. This study was designed to evaluate the tolerability of inhaled N-chlorotaurine (NCT) in the pig model.
Protozoan parasites of the genus Leishmania are the causative agents of life-threatening visceral as well as cutaneous and mucocutaneous leishmaniasis. First-line drugs are antimonials, but toxicity and resistance in some endemic areas cause serious problems. In the current study, the antileishmanial activity of the weak oxidant N-chlorotaurine (NCT) was investigated. NCT is a derivative of the amino acid taurine produced by granulocytes and monocytes during oxidative burst, but can also be synthesized chemically and used topically as an antiseptic at a concentration of 1 % (55 mM) in vivo. NCT susceptibility tests were performed in vitro with promastigotes and amastigotes of Leishmania infantum and Leishmania donovani. As NH(4)Cl is known to increase the activity of NCT by the formation of monochloramine (NH(2)Cl), co-treatment assays were included in the study. Mean EC(50) values after 1 h of treatment were 5.94 mM for L. infantum and 9.8 mM for L. donovani promastigotes. Co-treatment with 5.5 mM NCT plus 19 mM NH(4)Cl led to complete killing of promastigotes of both strains within 15 min. Amastigotes were inactivated by treatment with 2 mM NCT alone. The results of this study indicate a high potential of NCT against Leishmania species.
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.
The activity of oxidants, such as halogens and active halogen compounds, decreases generally in the presence of proteinaceous material. A quantification of consumption effects was performed to judge the suitability of different representatives as antiseptics and their compatibility with pharmaceutical additives.
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