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

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.

Identification of Point Mutations in Clinical Staphylococcus aureus Strains That Produce Small-Colony Variants Auxotrophic for Menadione

“…In the majority of Gram-positive bacteria, menaquinone is the only quinone in the electron transport chain, making the enzymes that synthesize this compound promising drug targets for multidrug-resistant pathogens such as S. aureus and Mycobacterium tuberculosis (34). In this regard, we note that growth inhibition has been reported for compounds that target the gene products of menA (34,36), menD (16), menE (18), and menB (37). The initial findings for this new class of antimicrobial molecules highlight the importance of the work presented here.…”

“…Many of the typical SCV characteristics (e.g., low growth rate, lack of pigmentation, increased aminoglycoside resistance, and decreased alpha-toxin production) can be linked to electron transport deficiencies (reviewed in reference 11). Most studies investigating SCVs have used laboratory strains containing stable mutations in the menD or hemB gene, resulting in menadione-and hemin-auxotrophic strains, respectively, the two most common SCV phenotypes (16)(17)(18).…”

A Bicarbonate Cofactor Modulates 1,4-Dihydroxy-2-naphthoyl-Coenzyme A Synthase in Menaquinone Biosynthesis of Escherichia coli

“…This naphthoquinone is synthesized from the chorismate of the shikimate pathway in microorganisms (1, 2, 7, 8), whereas it has to be acquired from diet or intestinal microflora in humans or animals (9, 10). Due to its absence in humans and animals, menaquinone biosynthesis has been an attractive target for development of antibiotics against a number of important microbial pathogens, such as Mycobacterium tuberculosis and Staphylococcus aureus (11,12).Menaquinone biosynthesis has been most extensively studied in the facultative anaerobe Escherichia coli that uses the naphthoquinone (MK-8) and its demethylated congener (demethylmenaquinone, DMK-8) as an obligatory electron transporter under anaerobic conditions when the electron acceptor is fumarate, dimethyl sulfoxide, or trimethylamine N-oxide (13,14). The naphthoquinone level is significantly up-regulated during the aerobiosis-to-anaerobiosis transition (15-17), indicating that menaquinone biosynthesis is subject to aeration control.…”

“…This naphthoquinone is synthesized from the chorismate of the shikimate pathway in microorganisms (1, 2, 7, 8), whereas it has to be acquired from diet or intestinal microflora in humans or animals (9, 10). Due to its absence in humans and animals, menaquinone biosynthesis has been an attractive target for development of antibiotics against a number of important microbial pathogens, such as Mycobacterium tuberculosis and Staphylococcus aureus (11,12).…”

“…Due to its absence in humans and animals, menaquinone biosynthesis has been an attractive target for development of antibiotics against a number of important microbial pathogens, such as Mycobacterium tuberculosis and Staphylococcus aureus (11,12).…”