Potent Inhibition of E. coli DXP Synthase by a gem-Diaryl Bisubstrate Analog

Coco, Lauren B.; Toci, Eucolona M.; Chen, Percival Yang-Ting; Drennan, Catherine L.; Freel Meyers, Caren L.

doi:10.1021/acsinfecdis.3c00734

Title: Potent Inhibition of E. coli DXP Synthase by a gem-Diaryl Bisubstrate Analog

Journal Article · 20 March 2024 · ACS Infectious Diseases

DOI: https://doi.org/10.1021/acsinfecdis.3c00734 · OSTI ID:2470123

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Johns Hopkins Univ., Baltimore, MD (United States). School of Medicine
Massachusetts Inst. of Technology (MIT), Cambridge, MA (United States)

New antimicrobial strategies are needed to address pathogen resistance to currently used antibiotics. Bacterial central metabolism is a promising target space for the development of agents that selectively target bacterial pathogens. 1-Deoxy-_D-xylulose 5-phosphate synthase (DXPS) converts pyruvate and d-glyceraldehyde 3-phosphate (_D-GAP) to DXP, which is required for synthesis of essential vitamins and isoprenoids in bacterial pathogens. Thus, DXPS is a promising antimicrobial target. Toward this goal, our lab has demonstrated selective inhibition of Escherichia coli DXPS by alkyl acetylphosphonate (alkylAP)-based bisubstrate analogs that exploit the requirement for ternary complex formation in the DXPS mechanism. Here, we present the first DXPS structure with a bisubstrate analog bound in the active site. Insights gained from this cocrystal structure guided structure–activity relationship studies of the bisubstrate scaffold. A low nanomolar inhibitor (compound 8) bearing a gem-dibenzyl glycine moiety conjugated to the acetylphosphonate pyruvate mimic via a triazole-based linker emerged from this study. Compound 8 was found to exhibit slow, tight-binding inhibition, with contacts to E. coli DXPS residues R99 and R478 demonstrated to be important for this behavior. This work has discovered the most potent DXPS inhibitor to date and highlights a new role of R99 that can be exploited in future inhibitor designs toward the development of a novel class of antimicrobial agents.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 2470123

Journal Information:: ACS Infectious Diseases, Journal Name: ACS Infectious Diseases Journal Issue: 4 Vol. 10; ISSN 2373-8227

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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Title: Potent Inhibition of E. coli DXP Synthase by a gem-Diaryl Bisubstrate Analog

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