Stable Analogues of OSB-AMP: Potent Inhibitors of MenE the o-succinylbenzoate-CoA Synthetase from Bacterial Menaquinone Biosynthesis
MenE, the o-succinylbenzoate (OSB)-CoA synthetase from bacterial menaquinone biosynthesis, is a promising new antibacterial target. Sulfonyladenosine analogues of the cognate reaction intermediate, OSB-AMP, have been developed as inhibitors of the MenE enzymes from Mycobacterium tuberculosis (mtMenE), Staphylococcus aureus (saMenE) and Escherichia coli (ecMenE). Both a free carboxylate and a ketone moiety on the OSB side chain are required for potent inhibitory activity. OSB-AMS (4) is a competitive inhibitor of mtMenE with respect to ATP (K{sub i} = 5.4 {+-} 0.1 nM) and a noncompetitive inhibitor with respect to OSB (K{sub i} = 11.2 {+-} 0.9 nM). These data are consistent with a Bi Uni Uni Bi Ping-Pong kinetic mechanism for these enzymes. In addition, OSB-AMS inhibits saMenE with K{sub i}{sup app} = 22 {+-} 8 nM and ecMenE with K{sub i}{sup OSB} = 128 {+-} 5 nM. Putative active-site residues, Arg222, which may interact with the OSB aromatic carboxylate, and Ser302, which may bind the OSB ketone oxygen, have been identified through computational docking of OSB-AMP with the unliganded crystal structure of saMenE. A pH-dependent interconversion of the free keto acid and lactol forms of the inhibitors is also described, along with implications for inhibitor design.
- Research Organization:
- BROOKHAVEN NATIONAL LABORATORY (BNL)
- Sponsoring Organization:
- ELI LILLY & COMPANY
- DOE Contract Number:
- AC02-98CH10886
- OSTI ID:
- 1041625
- Report Number(s):
- BNL--96914-2012-JA; 600301010
- Journal Information:
- ChemBioChem, Journal Name: ChemBioChem Journal Issue: 1 Vol. 13; ISSN 1439-4227
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
60 APPLIED LIFE SCIENCES
ANTIBIOTICS
AROMATICS
BIOSYNTHESIS
CHAINS
CRYSTAL STRUCTURE
DESIGN
ENZYMES
ESCHERICHIA COLI
KETO ACIDS
KETONES
KINETICS
LIGASES
MYCOBACTERIUM TUBERCULOSIS
OXYGEN
REACTION INTERMEDIATES
RESIDUES
STAPHYLOCOCCUS
adenylation
antibiotics
docking
drug design
inhibitors