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Screening for novel anti-trypanosomal drugs through metabolomic tools

Edrada-Ebel, Ruangelie (2011) Screening for novel anti-trypanosomal drugs through metabolomic tools. In: Deutsch-Brasilianischen Jahres der Wissenschaft, Technologie und Innovation (DBWTI), 2011-04-26 - 2011-04-28.

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Abstract

There is a drastic need for new and improved anti-trypanosomal drugs to be developed due to the alarming rate of resurgence of trypanosomiasis, development of drug resistance, lack of efficacy of chemotherapy, drug-related adverse effects and drawbacks of the existing useful drugs. A novel, affordable, safe, and efficacious anti-trypanosomal drug should be to able combat the almost neglected yet life-threatening trypanosomiasis. We have established metabolomic methods to screen diverse biological sources of potentially novel and sustainable sources of antitrypanosomal drugs. Metabolomic profiling was done on organic extracts of diverse natural sources by using high resolution LCFTMS and NMR. The secondary metabolite profiles of anti-trypanosomal acitve extracts were then compared to those of the inactive samples with the aid of SIEVE and MZmine, both are automated label-free differential expression softwares. Together with high resolution NMR, principal component analysis and off-line databases were utilised to identify resonances that quantifies and confirms the presence of the secondary metabolite of interest. Preliminary highthroughput chromatographic separation of the active secondary metabolites was achieved on the active extracts exhibiting an interesting chemical profile. From African propolis we have identified active extracts to contain new highly oxygenated phloroglucinol derivatives. Tools of metabolomics were also applied to biotechnologically optimize the production of bioactive secondary metabolites in marine-derived fungi and endophytes. At small scales, efficient cultivation processes are developed to later scale-up to a fermenter system. Through tools of metabolomics and genomics, the production of other potential novel drugs can be optimised to solve and come up with a sustainable solution to address the supply problem. A novel anti-trypanosomal active macrolide lactone from a Streptomyces spp. was derived from the sponge Haliclona collected from the Irish Sea. Metabolomic studies through SIEVE showed that amino acid catabolism is an important source of building blocks for macrolide formation. Amino acid utilization is regulated through the process, which indirectly regulates macrolide biosynthesis.