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Antimicrobial Agents and Chemotherapy, December 2009, p. 5259-5264, Vol. 53, No. 12
0066-4804/09/$08.00+0     doi:10.1128/AAC.00662-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Polyamine Transport as a Target for Treatment of Pneumocystis Pneumonia

Chung-Ping Liao,¹ Otto Phanstiel IV,² Mark E. Lasbury,¹ Chen Zhang,¹ Shoujin Shao,^1,3 Pamela J. Durant,¹ Bi-Hua Cheng,⁴ and Chao-Hung Lee^1,5*

Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202,¹ Department of Medical Education, University of Central Florida, Orlando, Florida 32816,² Department of Obstetrics and Gynecology, Beijing Hospital, Beijing, China,³ Graduate Institute of Medical Science, Chang Gung University and Department of Obstetrics and Gynecology, Kaohsiung Medical Center, Chang Gung Memorial Hospital, Taipei, Taiwan,⁴ Graduate Institute of Clinical Medical Science and Department of Laboratory Medicine, China Medical University, Taichung, Taiwan⁵

Received 14 May 2009/ Returned for modification 10 July 2009/ Accepted 20 September 2009

Polyamine levels are greatly increased in alveolar macrophages (AMs) during Pneumocystis pneumonia (PCP), leading to increased production of H₂O₂, which causes AMs to undergo apoptosis. One of the mechanisms by which polyamine levels in AMs are elevated is enhanced uptake of exogenous polyamines. In this study, the possibility of targeting polyamine uptake as a treatment for PCP was examined. Four anthracene- and one benzene-polyamine conjugates that are potential polyamine transport inhibitors, including N1-anthracen-9-ylmethyl-butane-1,4-diamine; N-(4-aminobutyl)-N-anthracen-9-ylmethylbutane-1,4-diamine; N-[4-(4-aminobutylamino)butyl]-N-anthracen-9-ylmethylbutane-1,4-diamine; N-(4-amino-butyl)-N'-(10-{[4-(4-amino-butylamino)butylamino]-methyl}anthracen-9-ylmethyl)butane-1,4-diamine (44-Ant-44); and benzene-polyamine conjugate N-(4-amino-butyl)-N'-(4-{[4-(4-amino-butylamino)butylamino]-methyl}benzyl)butane-1,4-diamine (44-Bn-44), were tested. Compounds 44-Ant-44 and 44-Bn-44 were found to have a very low toxicity to AMs in vitro and were evaluated for their therapeutic effect on PCP in vivo. Sprague-Dawley rats infected with P. carinii for 28 days were intranasally instilled with 50 µl of a 1 mM solution of 44-Bn-44 or 44-Ant-44 every 2 days. Twenty-one days after initiation of the treatment, three to five rats from each group were sacrificed and examined for lung pathology, organism burden, and apoptosis of AMs. Both 44-Bn-44 and 44-Ant-44 reduced organism burdens; however, only 44-Ant-44 decreased the severity of the infection with reduced lung inflammation, increased clearance of exudates, increased air space, and decreased apoptosis of AMs. 44-Ant-44 also significantly prolonged the survival of treated animals. These results suggest that polyamine uptake is a potential target for treatment of PCP.

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* Corresponding author. Mailing address: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, 1120 South Dr., FH419, Indianapolis, IN 46202. Phone: (317) 274-2596. Fax: (317) 278-0643. E-mail: chlee{at}iupui.edu

Published ahead of print on 5 October 2009.

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Antimicrobial Agents and Chemotherapy, December 2009, p. 5259-5264, Vol. 53, No. 12
0066-4804/09/$08.00+0     doi:10.1128/AAC.00662-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.