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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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Coumarins in the 139-compound polyketide-based library.
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pone-0103598-g007: Coumarins in the 139-compound polyketide-based library.

Mentions: Coumarins are a large class of phenolic substances made of fused benzene and α-pyrone rings, which constitute the core skeleton of many flavonoid compounds. The library contained eight coumarins (Figure 7) but only 7-hydroxycoumarin and aesculin showed significant inhibition against efDHQase. It is possible that small perturbations to the coumarin structure greatly affected the binding to efDHQase. Both compounds did not inhibit the growth of E. facaelis. 7-Hydroxycoumarin was previously found to have antimicrobial properties against Paecilomyces fulva, a plant pathogen that causes Byssochlamys rot on strawberries [37]. Aesculin was previously shown not to have antimicrobial activity against S. aureus, E.coli, and P. aeruginosa[38].


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)

Coumarins in the 139-compound polyketide-based library.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0103598-g007: Coumarins in the 139-compound polyketide-based library.
Mentions: Coumarins are a large class of phenolic substances made of fused benzene and α-pyrone rings, which constitute the core skeleton of many flavonoid compounds. The library contained eight coumarins (Figure 7) but only 7-hydroxycoumarin and aesculin showed significant inhibition against efDHQase. It is possible that small perturbations to the coumarin structure greatly affected the binding to efDHQase. Both compounds did not inhibit the growth of E. facaelis. 7-Hydroxycoumarin was previously found to have antimicrobial properties against Paecilomyces fulva, a plant pathogen that causes Byssochlamys rot on strawberries [37]. Aesculin was previously shown not to have antimicrobial activity against S. aureus, E.coli, and P. aeruginosa[38].

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