Effect of a Bis-Benzyl Polyamine Analogue on Pneumocystis carinii

Abstract

Pneumocystis carinii is the causative agent of P. carinii pneumonia (PCP), an opportunistic infection associated with AIDS and other immunosuppressed conditions. Although polyamine metabolism of this fungus has been shown to be a chemotherapeutic target, this metabolism has not been thoroughly investigated. Reported here is the effect of one polyamine analogue, N,N-bis{3-[(phenylmethyl)amino]propyl}-1,7-diaminoheptane (BBS), on P. carinii. BBS inhibits the growth of P. carinii in culture, but at concentrations higher than those required to inhibit the growth of other pathogens. However, BBS is at least as active in an animal model of PCP as in other models of diseases studied. BBS causes some reduction in P. carinii polyamine content and polyamine biosynthetic enzyme activities, but the effect is less than that observed with other pathogens and very much less than the effect of the polyamine biosynthesis inhibitor DL-␣-difluoromethylornithine. BBS enters P. carinii cells via a polyamine transporter, unlike all other cells that have been studied. P. carinii cells do not remove the benzyl groups of BBS, as is reported for mammalian cells. The most likely mode of action is displacement of natural polyamines. Overall, the activity of BBS provides further evidence that polyamines and polyamine metabolism are rational targets for the development of drugs to treat PCP. Because the details of BBS-P. carinii interaction differ from those of other cells studied, polyamine analogues may provide a highly specific treatment for PCP.Polyamine metabolism has been demonstrated to be a chemotherapy target for Pneumocystis carinii pneumonia (PCP) caused by the fungus P. carinii, a common opportunistic pathogen associated with AIDS, cancer chemotherapy, treatment for rheumatic disease, and other immunosuppressed conditions (12). Although there are many compounds that can be used to interfere with polyamine metabolism, most of the clinical and much of the experimental animal data to date have been obtained with DL-␣-difluoromethylornithine (DFMO; eflornithine), a compound which inhibits the critical polyamine biosynthetic enzyme ornithine decarboxylase (ODC). However, there are inhibitors of other polyamine biosynthetic steps as well as compounds which cause the acceleration of polyamine degradation or interfere with polyamine function (21). Among these is a series of bis-benzyl polyamine analogues synthesized by Merrell Dow Pharmaceuticals (now incorporated into Aventis). Here we report an examination of a bis-benzyl derivative, MDL-27695, N,NЈ-bis{3-[(phenylmethyl)amino]propyl}-1,7-diaminoheptane (BBS) [C 6 H 5 CH 2 NH(CH 2 ) 3 NH(CH 2 ) 7 NH(CH 2 ) 3 NHCH 2 C 6 H 5 ], for the ability to modulate the polyamine concentrations of P. carinii, to induce the polyamine catabolic enzyme spermine-spermidine acetyltransferase (SSAT), to block growth in vitro, and to treat an animal model of PCP. We found BBS to be active against P. carinii, thus demonstrating that polyamine analogues are a lead in the search for new compounds to treat PCP...

Mechanism and Tissue Specificity of Nicotine-mediated Lung S-Adenosylmethionine Reduction

“…Pneumocystis is an opportunistic fungus causing Pneumocystis pneumonia (PCP) 2 in people immunosuppressed because of AIDS, cancer chemotherapy, treatment to prevent transplant rejection, treatment for rheumatic diseases, severe malnutrition, etc. S-Adenosylmethionine (AdoMet) is a critical biochemical intermediate serving both as the methyl donor for a myriad of biochemical events and as the aminopropyl donor for polyamine synthesis.…”

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

“…In contrast, in P. carinii, MDL 27695 was not metabolized to the 3-7-3 derivative, and the debenzylated product (3-7-3 amine) was not growth inhibitory, indicating that the intact molecule was responsible for the antipneumocystis effects (20). In the present study, BW-1 was taken up and rapidly oxidized to apparently identical products by E. cuniculi and the uninfected RK-13 feeder cells.…”

“…The potential utility of MDL 27695 has been demonstrated as an inhibitor of mammalian tumor cell growth and as an antimalarial and antileishmanial agent (6,9,23). Recent studies with MDL 27695 against Pneumocystis carinii indicate that MDL 27695 was highly effective in a rat model of infection and interfered with the polyamine uptake and metabolism of the parasite (20).…”

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

“…and, to a lesser extent, E. bieneusi infections, but there have been reports of relapse and toxicity associated with the systemic administration of fumagillin (4,16,21). Polyamine analogs have recently been applied experimentally as chemotherapeutic agents against opportunistic pathogens, including Pneumocystis jirovecii (18), Cryptosporidium parvum (32), and E. cuniculi (1). E. bieneusi is clinically the most common microsporidian species associated with a serious disease in humans, yet so little is known about the metabolism of the parasite.…”