The redox cofactor menaquinone is an essential component of the electron transport chain and enzymes in the menaquinone biosynthesis pathway are promising targets for antibacterial drug discovery. Currently, we have identified several classes of inhibitors using HTS that target the 1,4-dihydroxynaphthoyl-CoA synthases (MenB) in Mycobacterium tuberculosis and Staphylococcus aureus. The most potent series of compounds operate as prodrugs, and react with coenzyme A in situ to form the active drug molecule. SAR studies together with data from X-ray crystallography are being utilized to optimize the potency and antibacterial activity of these compounds and to make them more drug-like. Currently, the most potent compounds have MIC values of 0.65 and 0.5 mg/ml against M. tuberculosis and S. aureus, respectively. Target validation experiments demonstrate that these compounds decrease the menaquinone content in S. aureus.

Inhibition of the menaquinone biosynthesis pathway: A novel chemotherapeutic approach to treat <i>Mycobacterium tuberculosis</i> and <i>Staphylococcus aureus</i>

241st National Meeting (2011)

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Inhibition of the menaquinone biosynthesis pathway: A novel chemotherapeutic approach to treat Mycobacterium tuberculosis and Staphylococcus aureus