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Synthesis of Bisindole Alkaloids and Their Mode of Action against Methicillin-Resistant Staphylococcus Aureus .
- Source :
-
ACS infectious diseases [ACS Infect Dis] 2024 Jun 14; Vol. 10 (6), pp. 1958-1969. Date of Electronic Publication: 2024 Jun 06. - Publication Year :
- 2024
-
Abstract
- 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.
- Subjects :
- Humans
Staphylococcal Infections drug therapy
Staphylococcal Infections microbiology
Cell Line
Structure-Activity Relationship
Indoles pharmacology
Indoles chemistry
Indoles chemical synthesis
Molecular Structure
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
Subjects
Details
- Language :
- English
- ISSN :
- 2373-8227
- Volume :
- 10
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- ACS infectious diseases
- Publication Type :
- Academic Journal
- Accession number :
- 38841740
- Full Text :
- https://doi.org/10.1021/acsinfecdis.3c00657