? The Microsporidia are a group of intracellular parasitic protozoa of the phylum Microspora. These organisms are emerging as human pathogens primarily affecting immunosuppressed hosts (e.g., those with AIDS). Pathogenic genera include Nosema, Encephalitozoon, Enterocytozoon, Brachiola and others. While human infections, particularly with the enteric pathogen Enterocytozoon bieneusi can be particularly devastating, effective, non-toxic chemotherapy for this and other microsporidial infections is lacking. In preliminary studies, we examined polyamine metabolism in the human pathogen Encephalitozoon cuniculi, and found the major natural polyamines putrescine, spermidine and spermine that are ubiquitous in cells and necessary for growth and division. We have found certain classes of polyamine analogues, developed as antitumor agents, are growth inhibitory in vitro and curative in a murine model of Enc. cuniculi infection. Although we have determined that Enc. cuniculi pre-emergent spores can synthesize polyamines from ornithine as well as take up spermine and back convert it to spermidine, we believe from this and related data, that spermidine uptake and interconversion is the primary means by which microsporidia acquire polyamines. We intend to continue our study of polyamine metabolism, investigating polyamine uptake and interconversion through the spermidine/spermine N' acetyltransferase (SSAT)/polyamine oxidase (PAO) pathway, and the mechanism of action of the polyamine analogues on Enc. cuniculi. This data can be used to guide our collaborating chemists in the synthesis of new agents. To accomplish this we intend to: i) define and characterize Enc. cuniculi SSAT/PAO, determining its inducibility, the effects of polyamine analogues on induction and the overall pathway; ii) define and characterize polyamine transport, particularly the structural limits of the sites and comparing known transporters from other systems to Eric. cuniculi; and iii) determine the mechanism of action of existing polyamine analogues curative for Eric. cuniculi, i.e. whether their metabolism by host or parasite enzymes is essential for activity. We believe that by integrating the results of the SSAT/PAO and uptake studies, we will be able to develop more potent and specific polyamine analogues as chemotherapeutic agents, identify other polyamine metabolic targets in the Microsporidia for chemotherapeutic intervention, while providing basic information on the biochemistry and genomics of these obligate intracellular pathogens. ? ? ?
| Bacchi, C J; Yarlett, N; Weiss, L M (2003) Polyamine metabolism in the Microsporidia. Biochem Soc Trans 31:420-3 |
| Bacchi, Cyrus J; Weiss, Louis M; Lane, Schenella et al. (2002) Novel synthetic polyamines are effective in the treatment of experimental microsporidiosis, an opportunistic AIDS-associated infection. Antimicrob Agents Chemother 46:55-61 |
| Bacchi, C J; Yarlett, N (2002) Polyamine metabolism as chemotherapeutic target in protozoan parasites. Mini Rev Med Chem 2:553-63 |
| Bacchi, C J; Lane, S; Weiss, L M et al. (2001) Polyamine synthesis and interconversion by the Microsporidian Encephalitozoon cuniculi. J Eukaryot Microbiol 48:374-81 |
| Zou, Y; Wu, Z; Sirisoma, N et al. (2001) Novel alkylpolyamine analogues that possess both antitrypanosomal and antimicrosporidial activity. Bioorg Med Chem Lett 11:1613-7 |
