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

Cheung VW, Xue B, Hernandez-Valladares M, Go MK, Tung A, Aguda AH, Robinson RC, Yew WS - PLoS ONE (2014)

Bottom Line: 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".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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.

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.

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The DHQase reaction.
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pone-0103598-g001: The DHQase reaction.

Mentions: 3-Dehydroquinate dehydratase (DHQase) is the third enzyme in the shikimate pathway. DHQase catalyzes the dehydration of 3-dehydroquinate to 3-dehydroshikimate (Figure 1). There are two types of DHQase: type I enzymes catalyze a Schiff base mechanism using a catalytic lysine residue; type II DHQase catalyze the dehydration reaction via an enolate intermediate. DHQase from Enterococcus faecalis is a type I enzyme. Other organisms that have type I DHQases include Eschericia coli[6], Salmonella typhi[7] and Shigella dysenteriae[8].


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

Cheung VW, Xue B, Hernandez-Valladares M, Go MK, Tung A, Aguda AH, Robinson RC, Yew WS - PLoS ONE (2014)

The DHQase reaction.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4114755&req=5

pone-0103598-g001: The DHQase reaction.
Mentions: 3-Dehydroquinate dehydratase (DHQase) is the third enzyme in the shikimate pathway. DHQase catalyzes the dehydration of 3-dehydroquinate to 3-dehydroshikimate (Figure 1). There are two types of DHQase: type I enzymes catalyze a Schiff base mechanism using a catalytic lysine residue; type II DHQase catalyze the dehydration reaction via an enolate intermediate. DHQase from Enterococcus faecalis is a type I enzyme. Other organisms that have type I DHQases include Eschericia coli[6], Salmonella typhi[7] and Shigella dysenteriae[8].

Bottom Line: 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".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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.

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.

Show MeSH
Related in: MedlinePlus