دورية أكاديمية
Synthesis of Bisindole Alkaloids and Their Mode of Action against Methicillin-Resistant Staphylococcus Aureus .
| العنوان: | Synthesis of Bisindole Alkaloids and Their Mode of Action against Methicillin-Resistant Staphylococcus Aureus . |
|---|---|
| المؤلفون: | Adeniyi ET; Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural Sciences, Institute of Pharmaceutical Biology and Biotechnology, Universitätsstraße 1, 40225 Düsseldorf, Germany., Kruppa M; Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural Sciences, Institute of Organic Chemistry and Macromolecular Chemistry, Universitätsstrasse 1, 40225 Düsseldorf, Germany., De Benedetti S; Institute for Pharmaceutical Microbiology, University Hospital Bonn, University of Bonn, 53115 Bonn, Germany., Ludwig KC; Institute for Pharmaceutical Microbiology, University Hospital Bonn, University of Bonn, 53115 Bonn, Germany., Krisilia V; Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural Sciences, Institute of Pharmaceutical Biology and Biotechnology, Universitätsstraße 1, 40225 Düsseldorf, Germany., Wassenberg TR; Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural Sciences, Institute of Organic Chemistry and Macromolecular Chemistry, Universitätsstrasse 1, 40225 Düsseldorf, Germany., Both M; Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural Sciences, Institute of Organic Chemistry and Macromolecular Chemistry, Universitätsstrasse 1, 40225 Düsseldorf, Germany., Schneider T; Institute for Pharmaceutical Microbiology, University Hospital Bonn, University of Bonn, 53115 Bonn, Germany., Müller TJJ; Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural Sciences, Institute of Organic Chemistry and Macromolecular Chemistry, Universitätsstrasse 1, 40225 Düsseldorf, Germany., Kalscheuer R; Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural Sciences, Institute of Pharmaceutical Biology and Biotechnology, Universitätsstraße 1, 40225 Düsseldorf, Germany. |
| المصدر: | ACS infectious diseases [ACS Infect Dis] 2024 Jun 14; Vol. 10 (6), pp. 1958-1969. Date of Electronic Publication: 2024 Jun 06. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: ACS Publications Country of Publication: United States NLM ID: 101654580 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2373-8227 (Electronic) Linking ISSN: 23738227 NLM ISO Abbreviation: ACS Infect Dis Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Washington, DC : ACS Publications, [2015]- |
| مواضيع طبية MeSH: | Methicillin-Resistant Staphylococcus aureus*/drug effects , Anti-Bacterial Agents*/pharmacology , Anti-Bacterial Agents*/chemical synthesis , Anti-Bacterial Agents*/chemistry , Microbial Sensitivity Tests* , Indole Alkaloids*/pharmacology , Indole Alkaloids*/chemistry , Indole Alkaloids*/chemical synthesis, Humans ; Staphylococcal Infections/drug therapy ; Staphylococcal Infections/microbiology ; Cell Line ; Structure-Activity Relationship ; Indoles/pharmacology ; Indoles/chemistry ; Indoles/chemical synthesis ; Molecular Structure |
| مستخلص: | About 100,000 deaths are attributed annually to infections with methicillin-resistant Staphylococcus aureus (MRSA) despite concerted efforts toward vaccine development and clinical trials involving several preclinically efficacious drug candidates. This necessitates the development of alternative therapeutic options against this drug-resistant bacterial pathogen. Using the Masuda borylation-Suzuki coupling (MBSC) sequence, we previously synthesized and modified naturally occurring bisindole alkaloids, alocasin A, hyrtinadine A and scalaradine A, resulting in derivatives showing potent in vitro and in vivo antibacterial efficacy. Here, we report on a modified one-pot MBSC protocol for the synthesis of previously reported and several undescribed N -tosyl-protected bisindoles with anti-MRSA activities and moderate cytotoxicity against human monocytic and kidney cell lines. In continuation of the mode of action investigation of the previously synthesized membrane-permeabilizing hit compounds, mechanistic studies reveal that bisindoles impact the cytoplasmic membrane of Gram-positive bacteria by promiscuously interacting with lipid II and membrane phospholipids while rapidly dissipating membrane potential. The bactericidal and lipid II-interacting lead compounds 5c and 5f might be interesting starting points for drug development in the fight against MRSA. |
| فهرسة مساهمة: | Keywords: MRSA; Masuda borylation-Suzuki coupling; Methicillin-resistant Staphylococcus aureus; antibacterial; bisindole; lipid II |
| المشرفين على المادة: | 0 (Anti-Bacterial Agents) 0 (Indole Alkaloids) 0 (Indoles) |
| تواريخ الأحداث: | Date Created: 20240606 Date Completed: 20240614 Latest Revision: 20240614 |
| رمز التحديث: | 20240614 |
| DOI: | 10.1021/acsinfecdis.3c00657 |
| PMID: | 38841740 |
| قاعدة البيانات: | MEDLINE |
Find this issue from the American Chemical Society | تدمد: | 2373-8227 |
|---|---|
| DOI: | 10.1021/acsinfecdis.3c00657 |