When bacteria are grown in media containing only carbon, nitrogen and essential salts, they shift in their metabolic activities to include the synthesis of essential amino acids, vitamins and other cofactors. Only 303 genes, for example, are essential for growth of E. coli on rich media and some 119 additional genes are required for growth on nutrient-limited media. Hence compounds that target bacteria under nutrient-limited conditions could serve as leads for novel antibacterial drugs. In fact, nutrient-limited media probably provide a better proxy for the host environment. There have been many reports of impaired growth and attenuated virulence in pathogens due to mutations in vitamin, nucleobase and amino acid biosynthetic genes. Nevertheless, systematic searches for antibacterial chemicals have overwhelmingly emphasized rich media conditions. Thus, there is a considerable gap in antibacterial chemical space surveyed to date. With the goal of targeting biosynthetic pathways, we have been screening libraries of structurally diverse synthetic compounds and natural products to find inhibitors of E. coli growth in minimal media. In this screening platform, synthetic compounds active in primary screens are subject to the addition of an array of key metabolites and pools thereof to identify suppressors of growth inhibition and provide hypotheses for physiological, genetic and biochemical experiments to elaborate mechanism of action. Natural products extracts on the other hand were found to contain nutrients that confounded this discovery platform. In this presentation, I will provide an account of on-going efforts to discover and characterize novel chemical matter targeting nutrient biosynthesis in bacteria, especially from natural sources.

Targeting bacterial nutrient biosynthesis with natural products

253rd National Meeting (2017)

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