Evaluation of Bacterial RNA Polymerase Inhibitors in a -Based Wound Infection Model in SKH1 Mice.
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Authors
Haupenthal, JörgKautz, Yannik
Elgaher, Walid A M
Pätzold, Linda
Röhrig, Teresa
Laschke, Matthias W
Tschernig, Thomas
Hirsch, Anna K H
Molodtsov, Vadim
Murakami, Katsuhiko S
Hartmann, Rolf W
Bischoff, Markus
Issue Date
2020-09-21
Metadata
Show full item recordAbstract
Chronic wounds infected with pathogens such as Staphylococcus aureus represent a worldwide health concern, especially in patients with a compromised immune system. As antimicrobial resistance has become an immense global problem, novel antibiotics are urgently needed. One strategy to overcome this threatening situation is the search for drugs targeting novel binding sites on essential and validated enzymes such as the bacterial RNA polymerase (RNAP). In this work, we describe the establishment of an in vivo wound infection model based on the pathogen S. aureus and hairless Crl:SKH1-Hrhr (SKH1) mice. The model proved to be a valuable preclinical tool to study selected RNAP inhibitors after topical application. While rifampicin showed a reduction in the loss of body weight induced by the bacteria, an acceleration of wound healing kinetics, and a reduced number of colony forming units in the wound, the ureidothiophene-2-carboxylic acid 1 was inactive under in vivo conditions, probably due to strong plasma protein binding. The cocrystal structure of compound 1 with RNAP, that we hereby also present, will be of great value for applying appropriate structural modifications to further optimize the compound, especially in terms of plasma protein binding.Citation
ACS Infect Dis. 2020 Oct 9;6(10):2573-2581. doi: 10.1021/acsinfecdis.0c00034. Epub 2020 Sep.Affiliation
HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.Publisher
American Chemical Society (ACS)Journal
ACS infectious diseasesPubMed ID
32886885Type
ArticleLanguage
enEISSN
2373-8227ae974a485f413a2113503eed53cd6c53
10.1021/acsinfecdis.0c00034
Scopus Count
The following license files are associated with this item:
- Creative Commons
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