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Antimicrobial Agents and Chemotherapy, June 2009, p. 2599-2604, Vol. 53, No. 6
0066-4804/09/$08.00+0     doi:10.1128/AAC.00267-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Metabolism of an Alkyl Polyamine Analog by a Polyamine Oxidase from the Microsporidian Encephalitozoon cuniculi{triangledown}

Cyrus J. Bacchi,1,2* Nigel Yarlett,1,3 Evangeline Faciane,1 Xiangdong Bi,4 Donna Rattendi,1 Louis M. Weiss,5 and Patrick M. Woster4

Haskins Laboratories,1 Departments of Biological and Health Sciences,2 Chemistry and Physical Sciences, Pace University, New York, New York 10038,3 Eugene Applebaum College of Pharmacy and Health Sciences, Department of Pharmaceutical Sciences, Wayne State University, Detroit, Michigan 48202,4 Departments of Medicine and Pathology, Albert Einstein College of Medicine, Bronx, New York 104615

Received 26 February 2008/ Returned for modification 7 May 2008/ Accepted 4 February 2009

Encephalitozoon cuniculi is a microsporidium responsible for systemic illness in mammals. In the course of developing leads to new therapy for microsporidiosis, we found that a bis(phenylbenzyl)3-7-3 analog of spermine, 1,15-bis{N-[o-(phenyl)benzylamino}-4,12-diazapentadecane (BW-1), was a substrate for an E. cuniculi amine oxidase activity. The primary natural substrate for this oxidase activity was N'-acetylspermine, but BW-1 had activity comparable to that of the substrate. As the sole substrate, BW-1 gave linear reaction rates over 15 min and Km of 2 µM. In the presence of N'-acetylspermine, BW-1 acted as a competitive inhibitor of oxidase activity and may be a subversive substrate, resulting in increased peroxide production. By use of 13C-labeled BW-1 as a substrate and nuclear magnetic resonance analysis, two products were determined to be oxidative metabolites, a hydrated aldehyde or dicarboxylate and 2(phenyl)benzylamine. These products were detected after exposure of 13C-labeled BW-1 to E. cuniculi preemergent spore preparations and to uninfected host cells. In previous studies, BW-1 was curative in a rodent model of infection with E. cuniculi. The results in this study demonstrate competitive inhibition of oxidase activity by BW-1 and support further studies of this oxidase activity by the parasite and host.

* Corresponding author. Mailing address: Haskins Laboratories, Pace University, 41 Park Row, New York, NY 10038. Phone: (212) 346-1886. Fax: (212) 346-1586. E-mail: cbacchi{at}pace.edu

{triangledown} Published ahead of print on 17 February 2009.

Antimicrobial Agents and Chemotherapy, June 2009, p. 2599-2604, Vol. 53, No. 6
0066-4804/09/$08.00+0     doi:10.1128/AAC.00267-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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