A study of inhibitors of d-glycero-β-d-manno-heptose-1-phosphate adenylyltransferase from Burkholderia pseudomallei as a potential antibiotic target

Suwon Kim, Seri Jo, Mi Sun Kim, Dong Hae Shin

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

d-Glycero-β-d-manno-heptose-1-phosphate adenylyltransferase from Burkholderia pseudomallei (BpHldC) is the fourth enzyme in the ADP‐l‐glycero‐β‐d‐manno‐heptose biosynthesis pathway producing a lipopolysaccharide core. Therefore, BpHldC is an anti-melioidosis target. Three ChemBridge compounds purchased from ChemBridge Corporation (San Diego, CA) were found to have an effective inhibitory activity on BpHldC. Interestingly, ChemBridge 7929959 was the most effective compound due to the presence of the terminal benzyl group. The enzyme kinetic study revealed that most of them show mixed type inhibitory modes against ATP and βG1P. The induced-fit docking indicated that the medium affinity of ChemBridge 7929959 is originated from its benzyl group occupying the substrate-binding pocket of BpHldC. The inhibitory role of terminal aromatic groups was proven with ChemBridge 7570508. Combined with the previous study, ChemBridge 7929959 is found to work as a dual inhibitor against both HldC and HddC. Therefore, three ChemBridge compounds can be developed as a potent anti-melioidosis agent with a novel inhibitory concept.

Original languageEnglish
Pages (from-to)776-784
Number of pages9
JournalJournal of Enzyme Inhibition and Medicinal Chemistry
Volume36
Issue number1
DOIs
StatePublished - 2021

Bibliographical note

Funding Information:
This work was supported by the Basic Science Research Programs, 2018R1D1A1B07050781 to DHS and 2018R1D1A1B07050942 to MK, funded by the National Research Foundation of Korea Grant granted by the Ministry of Education, Science and Technology, Republic of Korea (MEST). S. Jo was supported by Brain Korea 21 (BK21) Project.

Publisher Copyright:
© 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

Keywords

  • ADP‐l‐glycero‐β‐d‐manno‐heptose
  • Burkholderia pseudomallei
  • ChemBridge compounds
  • anti-melioidosis agent
  • d-Glycero-β-d-manno-heptose-1-phosphate adenylyltransferase

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