微生物学
抗菌剂
抗生素
最小抑制浓度
抗菌剂
药理学
立体化学
作者
Nidja Rehberg,Gereon A. Sommer,Daniel Drießen,Marco Kruppa,Emmanuel T Adeniyi,Shang Chen,Lin Wang,Karina Wolf,Boris O. A. Tasch,Thomas R. Ioerger,Kui Zhu,Thomas Müller,Rainer Kalscheuer
标识
DOI:10.1021/acs.jmedchem.0c00826
摘要
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.
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