A Methyl 4-Oxo-4-phenylbut-2-enoate within VivoActivity against MRSA that Inhibits MenB in the Bacterial Menaquinone Biosynthesis Pathway.
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 ofStaphylococcus aureus. Mode of action studies on the most potent compound, methyl 4-(4-chlorophenyl)-4-oxobut-2-enoate (1), reveal that1is converted into the corresponding CoA adduct inS. aureuscells, and that this adduct binds to theS. aureusMenB (saMenB) with aKdvalue of 2 µM. The antibacterial spectrum of1is limited to bacteria that utilize MK for respiration, and the activity of1can be complemented with exogenous MK or menadione. Finally, treatment of methicillin-resistantS. aureus(MRSA) with1results in the small colony variant phenotype and thus1phenocopies knockout of themenBgene. Taken together the data indicate that the antibacterial activity of1results from a specific effect on MK biosynthesis. We also evaluated thein vivoefficacy of1using two mouse models of MRSA infection. Notably, compound1increased 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.
Institute of Chemical Biology & Drug Discovery, Department of Chemistry, Stony Brook University, Stony Brook, NY, 11794-3400.
Joe S
JS
Matarlo
Institute of Chemical Biology & Drug Discovery, Department of Chemistry, Stony Brook University, Stony Brook, NY, 11794-3400.
Yang
Y
Lu
Institute of Chemical Biology & Drug Discovery, Department of Chemistry, Stony Brook University, Stony Brook, NY, 11794-3400.
Fereidoon
F
Daryaee
Institute of Chemical Biology & Drug Discovery, Department of Chemistry, Stony Brook University, Stony Brook, NY, 11794-3400.
Taraneh
T
Daryaee
Institute of Chemical Biology & Drug Discovery, Department of Chemistry, Stony Brook University, Stony Brook, NY, 11794-3400.
Bela
B
Ruzsicska
Institute of Chemical Biology & Drug Discovery, Department of Oral Biology and Pathology, Stony Brook University, Stony Brook, NY, 11794-3400.
Stephen G
SG
Walker
Institute of Chemical Biology & Drug Discovery, Department of Chemistry, Stony Brook University, Stony Brook, NY, 11794-3400.
Peter J
PJ
Tonge
DHNA; MenB; Menaquinone biosynthesis; Staphylococcus aureus; electrophilic antibacterial compound; menadione