Functional and structural basis of E. coli enolase inhibition by SF2312: a mimic of the carbanion intermediate

Krucinska, Jolanta; Lombardo, Michael N.; Erlandsen, Heidi; Hazeen, Akram; Duay, Searle S.; Pattis, Jason G.; Robinson, Victoria L.; May, Eric R.; Wright, Dennis L.

doi:10.1038/s41598-019-53301-3

Title: Functional and structural basis of E. coli enolase inhibition by SF2312: a mimic of the carbanion intermediate

Journal Article · 19 November 2019 · Scientific Reports

DOI: https://doi.org/10.1038/s41598-019-53301-3 · OSTI ID:1624507

Krucinska, Jolanta ^[1]; Lombardo, Michael N. ^[1]; Erlandsen, Heidi ^[2]; Hazeen, Akram ^[3]; Duay, Searle S. ^[4]; Pattis, Jason G. ^[5]; Robinson, Victoria L. ^[5]; May, Eric R. ^[5]; Wright, Dennis L. ^[6]

Univ. of Connecticut, Storrs, CT (United States). Dept. of Pharmaceutical Sciences
Univ. of Connecticut, Storrs, CT (United States). Center for Open Research Resources & Equipment (COR2E)
Univ. of Connecticut, Storrs, CT (United States). Dept. of Chemistry
Univ. of Connecticut, Storrs, CT (United States). Dept. of Chemistry
Univ. of Connecticut, Storrs, CT (United States). Dept. of Molecular and Cellular Biology
Univ. of Connecticut, Storrs, CT (United States). Dept. of Pharmaceutical Sciences; Univ. of Connecticut, Storrs, CT (United States). Dept. of Chemistry

Many years ago, the natural secondary metabolite SF2312, produced by the actinomycete Micromonospora, was reported to display broad spectrum antibacterial properties against both Gram-positive and Gram-negative bacteria. Recent studies have revealed that SF2312, a natural phosphonic acid, functions as a potent inhibitor of human enolase. The mechanism of SF2312 inhibition of bacterial enolase and its role in bacterial growth and reproduction, however, have remained elusive. In this work, we detail a structural analysis of E. coli enolase bound to both SF2312 and its oxidized imide-form. Our studies support a model in which SF2312 acts as an analog of a high energy intermediate formed during the catalytic process. Biochemical, biophysical, computational and kinetic characterization of these compounds confirm that altering features characteristic of a putative carbanion (enolate) intermediate significantly reduces the potency of enzyme inhibition. When SF2312 is combined with fosfomycin in the presence of glucose-6 phosphate, significant synergy is observed. This suggests the two agents could be used as a potent combination, targeting distinct cellular mechanism for the treatment of bacterial infections. Together, our studies rationalize the structure-activity relationships for these phosphonates and validate enolase as a promising target for antibiotic discovery.

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Research Organization:: SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: AC02-76SF00515; 1R21AI140734-01; R35-GM119762; P41GM103393

OSTI ID:: 1624507

Journal Information:: Scientific Reports, Vol. 9, Issue 1; ISSN 2045-2322

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 6 works

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