Extracts of bacterial culture broths have been the starting point for the development of numerous therapeutics. However, only a very small fraction of bacterial biosynthetic diversity is accessible through this strategy. We have developed a discovery approach that bypasses the culturing step entirely. This approach starts with bioinformatically predicting small molecule structures from the primary sequences of biosynthetic gene clusters. These structures are then chemically synthesized to give synthetic-bioinformatic natural products (syn-BNPs). Syn-BNPs are not meant to be exact replica of natural products; instead they are close structural mimics to facilitate the discvoery of bioactive molecular scaffolds. Using this approach, we produced syn-BNPs inspired by nonribosomal peptide synthetases (NRPS) found in the human and soil microbiomes and screened them against microbial pathogens. This approach has led to the discovery of new antibiotics against MRSA and multidrug-resistant <i>A. baumannii</i>, as well as a new antifungal agent against <i>C. albicans</i>. As DNA sequencing technology and prediction algorithms continue to improve, the syn-BNP approach is poised to uncover even more bioactive molecules in years to come.

Bioinformatics and chemistry join forces for antibiotics discovery

256th National Meeting (2018)

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