Mechanism of MenE Inhibition by Acyl-Adenylate Analogues and Discovery of Novel Antibacterial Agents

Matarlo, Joe S.; Evans, Christopher E.; Sharma, Indrajeet; Lavaud, Lubens J.; Ngo, Stephen C.; Shek, Roger; Rajashankar, Kanagalaghatta R.; French, Jarrod B.; Tan, Derek S.; Tonge, Peter J.

doi:10.1021/acs.biochem.5b00966

Title: Mechanism of MenE Inhibition by Acyl-Adenylate Analogues and Discovery of Novel Antibacterial Agents

Journal Article · 21 September 2015 · Biochemistry

DOI: https://doi.org/10.1021/acs.biochem.5b00966 · OSTI ID:1427864

Matarlo, Joe S. ^[1]; Evans, Christopher E. ^[2]; Sharma, Indrajeet ^[2]; Lavaud, Lubens J. ^[1]; Ngo, Stephen C. ^[1]; Shek, Roger ^[2]; Rajashankar, Kanagalaghatta R. ^[3]; French, Jarrod B. ^[1]; Tan, Derek S. ^[2]; Tonge, Peter J. ^[1]

Stony Brook Univ., NY (United States)
Memorial Sloan Kettering Cancer Center, New York, NY (United States)
Argonne National Lab. (ANL), Argonne, IL (United States)

MenE is an o-succinylbenzoyl-CoA (OSB-CoA) synthetase in the bacterial menaquinone biosynthesis pathway and is a promising target for the development of novel antibacterial agents. The enzyme catalyzes CoA ligation via an acyl-adenylate intermediate, and we have previously reported tight-binding inhibitors of MenE based on stable acyl-sulfonyladenosine analogues of this intermediate, including OSB-AMS (1), which has an IC₅₀ value of ≤25 nM for Escherichia coli MenE. Herein, we show that OSB-AMS reduces menaquinone levels in Staphylococcus aureus, consistent with its proposed mechanism of action, despite the observation that the antibacterial activity of OSB-AMS is ~1000-fold lower than the IC₅₀ for enzyme inhibition. To inform the synthesis of MenE inhibitors with improved antibacterial activity, we have undertaken a structure–activity relationship (SAR) study stimulated by the knowledge that OSB-AMS can adopt two isomeric forms in which the OSB side chain exists either as an open-chain keto acid or a cyclic lactol. Furthermore, these studies revealed that negatively charged analogues of the keto acid form bind, while neutral analogues do not, consistent with the hypothesis that the negatively charged keto acid form of OSB-AMS is the active isomer. X-ray crystallography and site-directed mutagenesis confirm the importance of a conserved arginine for binding the OSB carboxylate. Although most lactol isomers tested were inactive, a novel difluoroindanediol inhibitor (11) with improved antibacterial activity was discovered, providing a pathway toward the development of optimized MenE inhibitors in the future.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: National Inst. of Health (NIH); USDOE

Grant/Contract Number:: AC02-98CH10886

OSTI ID:: 1427864

Journal Information:: Biochemistry, Journal Name: Biochemistry Journal Issue: 42 Vol. 54; ISSN 0006-2960

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
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molecular structure
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Title: Mechanism of MenE Inhibition by Acyl-Adenylate Analogues and Discovery of Novel Antibacterial Agents

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