Back to Search Start Over

Synthesis of Bisindole Alkaloids and Their Mode of Action against Methicillin-Resistant Staphylococcus Aureus .

Authors :
Adeniyi ET
Kruppa M
De Benedetti S
Ludwig KC
Krisilia V
Wassenberg TR
Both M
Schneider T
Müller TJJ
Kalscheuer R
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.

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