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5. Nature-Inspired (di)Azine-Bridged Bisindole Alkaloids with Potent Antibacterial In Vitro and In Vivo Efficacy against Methicillin-Resistant Staphylococcus aureus

Author

Rehberg, Nidja, primary, Sommer, Gereon A., additional, Drießen, Daniel, additional, Kruppa, Marco, additional, Adeniyi, Emmanuel T., additional, Chen, Shang, additional, Wang, Lin, additional, Wolf, Karina, additional, Tasch, Boris O. A., additional, Ioerger, Thomas R., additional, Zhu, Kui, additional, Müller, Thomas J. J., additional, and Kalscheuer, Rainer, additional

Published
2020
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7. Nature-Inspired (di)Azine-Bridged Bisindole Alkaloids with Potent Antibacterial In Vitroand In VivoEfficacy against Methicillin-Resistant Staphylococcus aureus

Author

Rehberg, Nidja, Sommer, Gereon A., Drießen, Daniel, Kruppa, Marco, Adeniyi, Emmanuel T., Chen, Shang, Wang, Lin, Wolf, Karina, Tasch, Boris O. A., Ioerger, Thomas R., Zhu, Kui, Müller, Thomas J. J., and Kalscheuer, Rainer

Abstract

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 4jand 4nexhibited potent in vivoefficacy against MRSA in a mouse wound infection model. Although structurally related bisindoles were reported to specifically target pyruvate kinase in MRSA, antibacterial activity of 4jand 4nis independent of pyruvate kinase. Rather, these compounds lead to bacterial membrane permeabilization and cellular efflux of low-molecular-weight molecules.

Published
2020
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