Identification of polyketide inhibitors targeting 3-dehydroquinate dehydratase in the shikimate pathway of Enterococcus faecalis

Vivian Wing Ngar Cheung, Bo Xue, Maria Hernandez-Valladares, Maybelle Kho Go, Alvin Tung, Adeleke H. Aguda, Robert C. Robinson, Wen Shan Yew

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Due to the emergence of resistance toward current antibiotics, there is a pressing need to develop the next generation of antibiotics as therapeutics against infectious and opportunistic diseases of microbial origins. The shikimate pathway is exclusive to microbes, plants and fungi, and hence is an attractive and logical target for development of antimicrobial therapeutics. The Gram-positive commensal microbe, Enterococcus faecalis, is a major human pathogen associated with nosocomial infections and resistance to vancomycin, the "drug of last resort". Here, we report the identification of several polyketide-based inhibitors against the E. faecalis shikimate pathway enzyme, 3-dehydroquinate dehydratase (DHQase). In particular, marein, a flavonoid polyketide, both inhibited DHQase and retarded the growth of Enterococcus faecalis . The purification, crystallization and structural resolution of recombinant DHQase from E. faecalis (at 2.2 Å resolution) are also reported. This study provides a route in the development of polyketide-based antimicrobial inhibitors targeting the shikimate pathway of the human pathogen E. faecalis.

Original languageEnglish
Article numbere103598
JournalPloS one
Volume9
Issue number7
DOIs
Publication statusPublished - Jul 29 2014
Externally publishedYes

Fingerprint

3-dehydroquinate dehydratase
shikimate pathway
Polyketides
polyketides
Enterococcus faecalis
Pathogens
Anti-Bacterial Agents
Vancomycin
Crystallization
Fungi
Flavonoids
anti-infective agents
antibiotics
Purification
Vancomycin Resistance
microorganisms
therapeutics
cross infection
vancomycin
pathogens

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Cheung, V. W. N., Xue, B., Hernandez-Valladares, M., Go, M. K., Tung, A., Aguda, A. H., ... Yew, W. S. (2014). Identification of polyketide inhibitors targeting 3-dehydroquinate dehydratase in the shikimate pathway of Enterococcus faecalis. PloS one, 9(7), [e103598]. https://doi.org/10.1371/journal.pone.0103598

Identification of polyketide inhibitors targeting 3-dehydroquinate dehydratase in the shikimate pathway of Enterococcus faecalis. / Cheung, Vivian Wing Ngar; Xue, Bo; Hernandez-Valladares, Maria; Go, Maybelle Kho; Tung, Alvin; Aguda, Adeleke H.; Robinson, Robert C.; Yew, Wen Shan.

In: PloS one, Vol. 9, No. 7, e103598, 29.07.2014.

Research output: Contribution to journalArticle

Cheung, Vivian Wing Ngar ; Xue, Bo ; Hernandez-Valladares, Maria ; Go, Maybelle Kho ; Tung, Alvin ; Aguda, Adeleke H. ; Robinson, Robert C. ; Yew, Wen Shan. / Identification of polyketide inhibitors targeting 3-dehydroquinate dehydratase in the shikimate pathway of Enterococcus faecalis. In: PloS one. 2014 ; Vol. 9, No. 7.
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