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Antimicrobial Agents and Chemotherapy, June 2009, p. 2417-2423, Vol. 53, No. 6
0066-4804/09/$08.00+0     doi:10.1128/AAC.01113-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Therapeutic Evaluation of Polyamine Analogue Drug Candidates against Enterocytozoon bieneusi in a SCID Mouse Model{triangledown}

Xiaochuan Feng,1 Venudhar K. Reddy,2 Harriet Mayanja-Kizza,3 Louis M. Weiss,4 Laurence J. Marton,5 and Saul Tzipori1*

Division of Infectious Diseases, Tufts University Cummings School of Veterinary Medicine, North Grafton, Massachusetts 01536,1 Medigen Biosciences LLC, Madison, Wisconsin 53719,2 Department of Internal Medicine, Makerere University Medical School and Mulago Hospital, Kampala, Uganda,3 Department of Medicine and Pathology, Albert Einstein College of Medicine, Bronx, New York, 10461,4 Progen Pharmaceuticals, Inc., Redwood City, California 940655

Received 19 August 2008/ Returned for modification 26 September 2008/ Accepted 6 March 2009

Enterocytozoon bieneusi is the most common cause of chronic diarrhea in individuals with human immunodeficiency virus infection or AIDS, and there is no effective therapy. The inhibitory activities of polyamine analogues (PG-11157, PG-11158, and PG-11302) against E. bieneusi infection were evaluated in SCID mice preconditioned with anti-gamma interferon monoclonal antibody intraperitoneally (i.p.). Mice were challenged orally with 104 E. bieneusi spores, and groups of mice were treated orally or i.p. 14 days later for 7 days. The inhibitory activities of the drugs against infection were determined by enumerating the E. bieneusi spores in feces three times a week by an immunofluorescence assay. Immunohistochemistry staining confirmed the infection within enterocytes. Oral administration of the analogues PG-11157 (at 150 or 75 mg/kg of body weight/day) and PG-11302 (at 250 mg/kg/day) had significant inhibitory activity (96.2 to 99.6%) that was slightly better than that of fumagillin (1 mg/kg/day; 93.7%). The inhibitory activity with i.p. injection was significant only with PG-11302 at 20 mg/kg/day. While the treatments considerably reduced the levels of spore excretion, neither polyamine analogues nor fumagillin was able to completely eliminate E. bieneusi, as excretion reappeared within 7 days after the end of treatment. Drug toxicity was apparent during treatment, but it disappeared at the end of treatment. These results warrant further examination of the analogues PG-11157 and PG-11302.

* Corresponding author. Mailing address: Division of Infectious Diseases, Tufts University Cummings School of Veterinary Medicine, North Grafton, MA 01536. Phone: (508) 839-7955. Fax: (508) 839-7911. E-mail: saul.tzipori{at}tufts.edu

{triangledown} Published ahead of print on 16 March 2009.

Antimicrobial Agents and Chemotherapy, June 2009, p. 2417-2423, Vol. 53, No. 6
0066-4804/09/$08.00+0     doi:10.1128/AAC.01113-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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