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Antimicrobial Agents and Chemotherapy, July 2005, p. 2914-2920, Vol. 49, No. 7
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.7.2914-2920.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Antifolate Activity of Epigallocatechin Gallate against Stenotrophomonas maltophilia

María Dolores Navarro-Martínez,¹ Enma Navarro-Perán,¹ Juan Cabezas-Herrera,² Joaquín Ruiz-Gómez,³ Francisco García-Cánovas,¹ and José Neptuno Rodríguez-López^1*

Grupo de Investigación de Enzimología, Departamento de Bioquímica y Biología Molecular A, Facultad de Biología, Universidad de Murcia, E-30100 Espinardo,¹ Servicio de Análisis Clínicos,² Servicio de Microbiología, Hospital Universitario Virgen de la Arrixaca, Murcia, Spain³

Received 7 October 2004/ Returned for modification 7 December 2004/ Accepted 6 March 2005

The catechin epigallocatechin gallate, one of the main constituents of green tea, showed strong antibiotic activity against 18 isolates of Stenotrophomonas maltophilia (MIC range, 4 to 256 µg/ml). In elucidating its mechanism of action, we have shown that epigallocatechin gallate is an efficient inhibitor of S. maltophilia dihydrofolate reductase, a strategic enzyme that is considered an attractive target for the development of antibacterial agents. The inhibition of S. maltophilia dihydrofolate reductase by this tea compound was studied and compared with the mechanism of a nonclassical antifolate compound, trimethoprim. Investigation of dihydrofolate reductase was undertaken with both a trimethoprim-susceptible S. maltophilia isolate and an isolate with a high level of resistance. The enzymes were purified using ammonium sulfate precipitation, gel filtration, and methotrexate affinity chromatography. The two isolates showed similar levels of dihydrofolate reductase expression and similar substrate kinetics. However, the dihydrofolate reductase from the trimethoprim-resistant isolate demonstrated decreased susceptibility to inhibition by trimethoprim and epigallocatechin gallate. As with other antifolates, the action of epigallocatechin gallate was synergistic with that of sulfamethoxazole, a drug that blocks folic acid metabolism in bacteria, and the inhibition of bacterial growth was attenuated by including leucovorin in the growth medium. We conclude that the mechanism of action of epigallocatechin gallate on S. maltophilia is related to its antifolate activity.

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* Corresponding author. Mailing address: Grupo de Investigación de Enzimología, Departamento de Bioquímica y Biología Molecular A, Facultad de Biología, Universidad de Murcia, E-30100 Espinardo, Murcia, Spain. Phone: 34-968-398284. Fax: 34-968-364147. E-mail: neptuno{at}um.es.

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Antimicrobial Agents and Chemotherapy, July 2005, p. 2914-2920, Vol. 49, No. 7
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.7.2914-2920.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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