Stable analogues of OSB-AMP: Potent inhibitors of MenE, the o-succinylbenzoate-CoA synthetase from bacterial menaquinone biosynthesis Journal Article


Authors: Lu, X.; Zhou, R.; Sharma, I.; Li, X.; Kumar, G.; Swaminathan, S.; Tonge, P. J.; Tan, D. S.
Article Title: Stable analogues of OSB-AMP: Potent inhibitors of MenE, the o-succinylbenzoate-CoA synthetase from bacterial menaquinone biosynthesis
Abstract: 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 (Ki=5.4±0.1 nM) and a noncompetitive inhibitor with respect to OSB (Ki=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 Kiapp = 22 ±8 nM and ecMenE with KiOSB =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. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Keywords: drug design; adenylation; inhibitors; antibiotics; docking
Journal Title: ChemBioChem
Volume: 13
Issue: 1
ISSN: 1439-4227
Publisher: Wiley V C H Verlag Gmbh  
Date Published: 2012-01-02
Start Page: 129
End Page: 136
Language: English
DOI: 10.1002/cbic.201100585
PROVIDER: scopus
PUBMED: 22109989
PMCID: PMC3436903
DOI/URL:
Notes: --- - "Export Date: 1 February 2012" - "CODEN: CBCHF" - "Source: Scopus"
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  1. Xuequan Lu
    7 Lu
  2. Derek S Tan
    91 Tan
  3. Indrajeet Sharma
    5 Sharma