Article
Pre-clinical development of the antibiotic Corallopyronin A
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Authors
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Andrea Schiefer
- University Hospital Bonn, Institute for Medical Microbiology, Immunology and Parasitology, Bonn; German Center for Infection Research (DZIF), partner site Bonn-Cologne, Bonn
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Anna Krome
- University of Bonn, Institute for Pharmaceutical Technology, Bonn
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Stefan Kehraus
- University of Bonn, Institute for Pharmaceutical Biology, Bonn
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Marc Hübner
- University Hospital Bonn, Institute for Medical Microbiology, Immunology and Parasitology, Bonn
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Stephan Hüttel
- Helmholtz Centre for Infection Research, Department Microbial Agents, Braunschweig
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Rolf Jansen
- Helmholtz Centre for Infection Research, Department Microbial Agents, Braunschweig
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Domen Pogorevc
- Helmholtz Institute for Pharmaceutical Research Saarland, Department Microbial Natural Products, Universitätscampus, Saarbrücken
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Till Schäberle
- University of Bonn, Institute for Pharmaceutical Biology, Bonn
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Martin Roth
- Leibniz Institute for Natural Product Research and Infection Biology, Hans-Knöll-Institute, Jena
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Gabriele M. König
- University of Bonn, Institute for Pharmaceutical Biology, Bonn
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Christian Keller
- Philips University of Marburg, Institute for Virology, Marburg
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Jan Rupp
- University of Lübeck, Department of Infectious Diseases and Microbiology, Lübeck
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Karl Wagner
- University of Bonn, Institute for Pharmaceutical Technology, Bonn
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Rolf Müller
- Helmholtz Institute for Pharmaceutical Research Saarland, Department Microbial Natural Products, Universitätscampus, Saarbrücken
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Marc Stadler
- Helmholtz Centre for Infection Research, Department Microbial Agents, Braunschweig
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Kenneth Pfarr
- University Hospital Bonn, Institute for Medical Microbiology, Immunology and Parasitology, Bonn; German Center for Infection Research (DZIF), partner site Bonn-Cologne, Bonn
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Achim Hoerauf
- University Hospital Bonn, Institute for Medical Microbiology, Immunology and Parasitology, Bonn; German Center for Infection Research (DZIF), partner site Bonn-Cologne, Bonn
| Published: | October 8, 2018 |
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Outline
Text
Corallopyronin A (CorA) is a natural product produced by Corallococcus coralloides that inhibits bacterial DNA-dependent RNA polymerase. Because CorA binds to the switch region and not in the active site, it is active against rifampicin-resistant S. aureus and MRSA. We have shown in vitro and in vivo CorA activity against Gram-negative Wolbachia intracellular bacteria, essential symbionts of filarial worms that cause lymphatic filariasis and onchocerciasis. Antiwolbachial therapy results in worm sterility and slow killing of worms. Importantly, CorA is also effective against Rickettsia spp., Chlamydia trachomatis, Neisseria gonorrhoeae and multi-resistant S. aureus (MIC 0.0625-1 µg/mL; nM range). The last three are targets on the WHO Sustainable Development Goals and Priority Pathogen List requiring new antibiotics. Using technical grade CorA we performed non-GLP ADME and in vitro toxicity studies that demonstrated: it has similar oral and intraperitoneal bioavailability; it has no overt toxicity and does not inhibit host cell proliferation; it does not significantly alter the expression of CYP450s and minimally induces CYP450 3A4 via PXR, thus drug-drug interactions comparable to rifampicin are not expected. CorA is stable in liver microsomes from dogs and humans for at least 45 minutes and is metabolized via phase I reactions resulting in oxidation metabolites. With our partners in the German Center for Infection Research (DZIF), we have successfully overcome a major hurdle frequently encountered with natural products, i.e. cost-efficient production, for which we have developed heterologous production in Myxococcus xanthus and a downstream process yielding CorA at >95% purity, confirmed by quantitative NMR and HPLC. Using CorA with >90% purity has lowered the effective regimen of the TPP recommended 7–14 days and is the only antiwolbachial drug that has consistent macrofilaricidal activity in animal models used by the MacDA and DNDi consortia for pre-clinical development of macrofilaricides. The final production protocol will provide CorA with a purity >90% for non-GLP pre-clinical studies, genotoxicity, hERG and non-GLP toxicity tests in 2018 and 2019. We are engaged with the competent German regulatory authority for advice on CorA specification for GMP production by a CMO in 2019 to conduct GLP-tox and safety studies, and to produce an oral formulation for a phase 1 trial.
References
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