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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