Tolerability and anti-infective activity of N-chlorotaurine

In this "Translational Research" project N-chlorotaurine, an endogenous antimicrobial agent, will be tested for its applicability in a special indication. Synthesis of the pure substance succeeded in our laboratory, and we proved its antiseptic-like microbicidal activity against bacteria, fungi, and viruses. Moreover, N-chlorotaurine is thought to be involved in termination of inflammation since it downregulates cytokines. It is very well tolerated by human tissue. Therapeutical efficacy has been proved in phase 2 clinical studies in purulently coated crural ulcers, otitis externa, and conjunctivitis so far. The microbicidal activity of N-chlorotaurine is enhanced by ammonium chloride. This opens the possibility to steer the efficacy of N-chlorotaurine. The first aim of this project is to prove the tolerability of N-chlorotaurine without and with ammonium chloride in an animal model. Anesthetized pigs will repeatedly be challenged with the test substances in different concentrations or saline (controls), and organ functions, blood oxygenation, and circulation will be monitored. Pharmacokinetics will be investigated by oxidation capacity and by determination of taurine and chloride in serum. Histology and electron microscopy of organ samples after euthanasia will be done to exclude tissue toxicity, and the in situ expression of cytokines will be investigated in an international cooperation. The second aim is to prove the tolerability and efficacy of N-chlorotaurine without and with ammonium chloride in the inflamed organ systems. Anesthetized pigs will be challenged (i) with meconium or (ii) with Streptococcus pyogenes. The test substances or saline will be applied subsequently, and the same parameters as mentioned above will be investigated. Bacterial counts of organ homogenates and exudates will be performed to quantify the in vivo antimicrobial activity. Importance of the project: Advantages of N-chlorotaurine are its tolerability and broad spectrum antimicrobial activity with absence of resistance development due to the unspecific mechanism of action. It can be conceived to be suitable for treatment of infections, particularly in difficult to treat ones, and for prophylaxis in immunosuppressed patients. The long-term perspectives are the application of the substance in these indications in human medicine and to arise interest of the pharmaceutical industry for funding and drug approval.