Metagenome mining to explore novel regions of natural products chemical space

Abstract

Genomics has accelerated discovery in biology in an unprecedented way. Still, we are far from solving grand challenges facing humanity. The challenge to combat antimicrobial resistance requires us to accelerate natural product discovery by several orders of magnitude. We are already running out of our existing arsenal of antibiotics and novel approaches are needed to accelerate the pace of their discovery and development. Quick screening of natural product biosynthesis potential via metagenome mining holds new hope to revive the antibiotic discovery pipeline. Thanks to recent advancements in next generation sequencing technologies and big data mining, now we can hope to rationally survey the diverse ecosystem metagenomes to discover novel secondary metabolites. In this thesis we have presented our developed metagenome data mining pipeline and approaches to explore novel regions of natural products chemical space. We present our results and insights from multiple ecosystem metagenome surveys. Novel biosynthesis genes, domains, cluster sequences and comparative patterns from the surveyed ecosystem are highlighted in separate chapters. Metagenome mining patterns from following diverse ecosystems were studied: 1) Different horizons of soil sampled from three sites in close vicinity from the Schoenbuch forest; 2) Lake Huron sediments; 3) human gut microbiome and 4) the Tuebingen actinomycetes strain collection. The insights gained from this thesis will be helpful to the natural products research community to accelerate metagenome based novel natural products discovery and revive the antibiotics discovery pipeline.