Mechanism-based inhibitors of MenE, an acyl-CoA synthetase involved in bacterial menaquinone biosynthesis

doi:10.1016/j.bmcl.2008.07.130

Bioorganic & Medicinal Chemistry Letters

Volume 18, Issue 22, 15 November 2008, Pages 5963-5966

https://doi.org/10.1016/j.bmcl.2008.07.130 Get rights and content

Abstract

Menaquinone (vitamin K₂) is an essential component of the electron transfer chain in many pathogens, including Mycobacterium tuberculosis and Staphylococcus aureus, and menaquinone biosynthesis is a potential target for antibiotic drug discovery. We report herein a series of mechanism-based inhibitors of MenE, an acyl-CoA synthetase that catalyzes adenylation and thioesterification of o-succinylbenzoic acid (OSB) during menaquinone biosynthesis. The most potent compound inhibits MenE with an IC₅₀ value of 5.7 μM.

Graphical abstract

The design, synthesis, and biochemical evaluation of mechanism-based OSB-CoA synthetase inhibitors is reported.

Section snippets

Acknowledgments

We thank Dr. George Sukenick, Hui Liu, Hui Fang, and Sylvi Rusli (MSKCC Analytical Core Facility) for expert mass spectral analyses. D.S.T. is an Alfred P. Sloan Research Fellow. Financial support from the NIH (R01 AI068038 to D.S.T.; R01 AI044639 and R21 AI058785 to P.J.T.), NYSTAR Watson Investigator Program (D.S.T.), William H. Goodwin and Alice Goodwin and the Commonwealth Foundation for Cancer Research, and MSKCC Experimental Therapeutics Center is gratefully acknowledged.

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Citation Excerpt :
A small set of sulfamates, sulfamides and vinyl sulfonamides (e.g., 54–57) was prepared as mimics of 53 and evaluated in a coupled enzyme assay (E.coli MenE and M.tb MenB), using the production of the MenB product, 1,4-dihydroxy-2-napthoyl-CoA as readout. The vinyl sulfonamide ketone 56 was the most effective MenE inhibitor in this assay (IC50 5.7 μM), six- to sevenfold better than 54 and 55, whereas its terminal alkene counterpart 57 was inactive.58 Unlabelled Image
The increasing prevalence of drug resistant tuberculosis has created an urgent need for new antibiotics with novel modes of action. New drug targets include various enzymes in the electron transport pathway that are critical for maintaining growth and survival of the causative bacterium. Following approval of the ATP synthase inhibitor bedaquiline, a large number of compounds with activity against these enzymes have been identified, and a few drug candidates were recently developed that are close to or have already commenced clinical trials. Such progress is indeed promising, although the predominant focus on just three targets (NADH dehydrogenase-2, QcrB in the cytochrome bc₁-aa₃ supercomplex, and ATP synthase) may need to be reconsidered in light of recent findings. In this chapter, we briefly review the role of each enzyme and summarize the key results for each inhibitor class.
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^☆: Dedicated to Professor Benjamin F. Cravatt, in honor of his outstanding contributions to chemical biology and his receipt of the 2008 Tetrahedron Young Investigator Award.

^†: These authors contributed equally to this work.

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Mechanism-based inhibitors of MenE, an acyl-CoA synthetase involved in bacterial menaquinone biosynthesis☆

Abstract

Graphical abstract

Section snippets

Acknowledgments

Bioorg. Med. Chem.

Curr. Opin. Microbiol.

Biochem. J.

Microbiol. Rev.

J. Biol. Chem.

Topics Curr. Chem.

Vitam. Horm.

Biochemistry

J. Bacteriol.

Gene

EMBO J.

Proc. Natl. Acad. Sci. U.S.A.

ChemBioChem

FEBS J.

Nat. Chem. Biol.

J. Med. Chem.

FEBS J.

Biochemistry

J. Am. Chem. Soc.

Chem. Biol.

ACS Chem. Biol.

J. Am. Chem. Soc.

Annu. Rev. Nutr.

J. Biol. Chem.

J. Bacteriol.

Mol. Microbiol.

Biochemistry

Biochemistry

Biochemistry

J. Biol. Chem.