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• W2300029921 abstract "4-Oxo-4-phenyl-but-2-enoates inhibit MenB, the 1,4-dihydroxyl-2-naphthoyl-CoA synthase in the bacterial menaquinone (MK) biosynthesis pathway, through the formation of an adduct with coenzyme A (CoA). Here, we show that the corresponding methyl butenoates have MIC values as low as 0.35-0.75 µg/mL against drug sensitive and resistant strains of Staphylococcus aureus. Mode of action studies on the most potent compound, methyl 4-(4-chlorophenyl)-4-oxobut-2-enoate (1), reveal that 1 is converted into the corresponding CoA adduct in S. aureus cells, and that this adduct binds to the S. aureus MenB (saMenB) with a Kd value of 2 µM. The antibacterial spectrum of 1 is limited to bacteria that utilize MK for respiration, and the activity of 1 can be complemented with exogenous MK or menadione. Finally, treatment of methicillin-resistant S. aureus (MRSA) with 1 results in the small colony variant phenotype and thus 1 phenocopies knockout of the menB gene. Taken together the data indicate that the antibacterial activity of 1 results from a specific effect on MK biosynthesis. We also evaluated the in vivo efficacy of 1 using two mouse models of MRSA infection. Notably, compound 1 increased survival in a systemic infection model and resulted in a dose-dependent decrease in bacterial load in a thigh infection model, validating MenB as a target for the development of new anti-MRSA candidates." @default.
• W2300029921 created "2016-06-24" @default.
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• W2300029921 creator A5079056895 @default.
• W2300029921 creator A5079719844 @default.
• W2300029921 creator A5087021225 @default.
• W2300029921 date "2016-03-18" @default.
• W2300029921 modified "2023-10-12" @default.
• W2300029921 title "A Methyl 4-Oxo-4-phenylbut-2-enoate with in Vivo Activity against MRSA That Inhibits MenB in the Bacterial Menaquinone Biosynthesis Pathway" @default.
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• W2300029921 doi "https://doi.org/10.1021/acsinfecdis.6b00023" @default.
• W2300029921 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/4898059" @default.
• W2300029921 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/27294200" @default.
• W2300029921 hasPublicationYear "2016" @default.
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