Nature-Inspired (di)Azine-Bridged Bisindole Alkaloids with Potent Antibacterial In Vitro and In Vivo Efficacy against Methicillin-Resistant Staphylococcus aureus
| Autor: | Nidja Rehberg, Lin Wang, Marco Kruppa, Thomas Müller, Karina Wolf, Thomas R. Ioerger, Boris O. A. Tasch, Gereon A. Sommer, Daniel Drießen, Rainer Kalscheuer, Kui Zhu, Shang Chen, Emmanuel T Adeniyi |
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| Rok vydání: | 2020 |
| Předmět: |
0303 health sciences
Chemistry medicine.disease_cause 01 natural sciences Methicillin-resistant Staphylococcus aureus In vitro 0104 chemical sciences 010404 medicinal & biomolecular chemistry 03 medical and health sciences Biochemistry In vivo Staphylococcus aureus Drug Discovery medicine Molecular Medicine Efflux Cytotoxicity Antibacterial activity Pyruvate kinase 030304 developmental biology |
| Zdroj: | Journal of Medicinal Chemistry. 63:12623-12641 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.0c00826 |
| Popis: | Natural bisindole alkaloids such as Hyrtinadine A and Alocasin A, which are known to exhibit diverse bioactivities, provide promising chemical scaffolds for drug development. By optimizing the Masuda borylation-Suzuki coupling sequence, a library of various natural product-derived and non-natural (di)azine-bridged bisindoles was created. While unsubstituted bisindoles were devoid of antibacterial activity, 5,5'-chloro derivatives were highly active against methicillin-resistant Staphylococcus aureus (MRSA) and further Gram-positive pathogens at minimal inhibitory concentrations ranging from 0.20 to 0.78 μM. These compounds showed strong bactericidal killing effects but only moderate cytotoxicity against human cell lines. Furthermore, the two front-runner compounds 4j and 4n exhibited potent in vivo efficacy against MRSA in a mouse wound infection model. Although structurally related bisindoles were reported to specifically target pyruvate kinase in MRSA, antibacterial activity of 4j and 4n is independent of pyruvate kinase. Rather, these compounds lead to bacterial membrane permeabilization and cellular efflux of low-molecular-weight molecules. |
| Databáze: | OpenAIRE |
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