ß,γ-Diaryl α-methylene-γ-butyrolactones as potent antibacterials against methicillin-resistant Staphylococcus aureus.
Bioorg Chem
; 104: 104183, 2020 11.
Article
em En
| MEDLINE
| ID: mdl-32971415
ABSTRACT
A selected series of racemic α-methylene-γ-butyrolactones (AMGBL) synthesized via allylboration or allylindation reactions were screened against methicillin-resistant Staphylococcus aureus (MRSA) USA300. Unlike natural AMGBLs, such as parthenolide, synthetic analogs bearing aryl moieties at the ß- and γ-positions are potent against MRSA. The most potent molecules were comparable to vancomycin and linezolid, the drugs of the last resort for MRSA infections, in their effectiveness with minimum inhibitory concentrations (MICs) ranging from 3.0 to 5.2⯵M. These lactones also exhibited potent antibacterial activity against other clinically important multidrug-resistant Gram-positive bacteria (except enterococci), while also showing high tolerability to mammalian cells. Several of these molecules surpassed vancomycin in their rapid killing of the high MRSA inoculum (2â¯h vs 12â¯h) in a standard time-kill kinetics assay, with compounds 1l and 1m significantly reducing the intracellular burden of MRSA by about 98-99%, at low concentrations. Additionally, the compounds surpassed vancomycin in inhibiting staphylococcal protease production, indicating that synthetic methylene lactones warrant further investigations as promising anti-MRSA candidates.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
4-Butirolactona
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Inibidores Enzimáticos
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Staphylococcus aureus Resistente à Meticilina
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Antibacterianos
Limite:
Animals
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article