Leishmaniasis is an endemic disease caused by the protozoan parasite Leishmania. Leishmaniasis affects approximately 0.9 million to 1.6 million people each year worldwide and incidences have been found in every continent except Australia and Antarctica. Current treatments for the parasite are limited by drug cost, availability and resistance as the occurrence of leishmaniasis continues to be more prevalent. Sulfonamides are a class of compounds with medicinal properties which have been used to treat bacterial and parasitic disease via various pathways. In our previous research, N-(2’-methylphenyl)-1-napthalene sulfonamide was found to inhibit Leishmania growth in vitro nearly 96% with a 100 uM addition in the log phase of cellular growth. Addition of folic acid provided protection against the inhibitory effects of this compound. Because the folic acid was seen to protect cell viability, the folic acid pathway was identified as a potential target for the inhibitory sulfonamide. The folic acid pathway is important for the production of tetrahydrofolate, which plays a major role in metabolic interconversions related to the transfer of one-carbon units. The folic acid pathway for Leishmania is complex, involving a bifunctional dihydrofolate reductase thymidylate synthase (DHFR-TS) enzyme for primary folic acid metabolism to tetrahydrofolate; however, a secondary pteridine reductase (PTR-1) enzyme is also available which can also reduce folic acid to tetrahydrofolate under optimal conditions. For this study, recombinant Leishmania major DHFR-TS, DHRF, and TS are inserted into E.coli and expressed. Enzyme kinetic studies, with and without the inhibitory sulfonamide, will be determined to assesses the effect of the sulfonamide on enzyme activity. Results from this work will help determine pathway of inhibition and applicability of the sulfonamide as a possible treatment for this disease.

Sulfonamide inhibition: Progress in determining pathway of inhibition in Leishmania

252nd National Meeting (2016)

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