Microbial genomics and strain prioritization to streamline natural product discovery

Traditional natural product discovery programs, relying primarily on bioassay-guided fractionation and chemical-profiling of compounds possessing unique structural novelty, are not sustainable because they demand too much time, effort, and resources.  The progress made in the last two decades in connecting natural products to the genes that encode their biosynthesis has fundamentally changed the landscape of natural products research and sparked the emergence of a suite of contemporary approaches to natural product discovery. While each of the various approaches has different strengths and weaknesses, they have been successful in yielding novel natural products but only on a case-by-case basis and are far from being of practical use for natural product discovery. Thus, in spite of the rapid advances in DNA sequencing technologies and bioinformatics, it is still unlikely to sequence and annotate all strains within a collection as a practical means to discover new natural products.  As the size of strain collections continues to grow, innovations in strains prioritization are clearly needed.  Resources could then be devoted preferentially to the strains that hold the highest promise in producing novel natural products.  Selected examples from our current efforts in prioritizing actinomycetals, thereby identifying the most promising strains for targeted discovery of novel natural products will be discussed.