| Summary: | In the course of a nearly century-long global effort to discover new bacterialderived drugs from the environment, there have been few innovations to the way that researchers have collected samples and subsequently created microbial libraries sourced for therapeutic discovery. Virtually every stage of the natural products (NP) drug discovery process has undergone a renaissance in method innovation: analytical detection of NPs, bioinformaticdriven discovery of NPs, detection, modification and expression of NP biosynthetic gene clusters, structure elucidation and dereplication of NPs and NP biological activity screening. Despite these advances, the philosophy we use to create microbial strain libraries from the environment (arguably the most important step) has seen little change in nearly eight decades of biomedical research. As a result, it is difficult to discover novel antibiotic scaffolds due to the degree of taxonomic and chemical redundancy that exists in these strain libraries, which has led to a divestment in microbialbased natural product drug discovery. To address the need for creating libraries with minimal taxa and NP overlap from environmental samples, we developed a high-throughput matrix assisted laser desorption ionization mass spectrometry (MALDI-TOF MS) based bioinformatics pipeline (IDBac) that allows us to readily group bacterial colonies by putative taxonomic identity and further discriminate them based on in situ natural product production. In addition to this, using a collection expedition to Iceland as an example, we purified all distinguishable bacterial colonies (1,616 total) off of isolation plates derived from 86 environmental samples and we employed the mass spectrometry (MS) based-IDBac workflow on these isolates to form groups of taxa (based on protein MS fingerprints; 3,000-15,000 Da), and further distinguished taxa subgroups based on their degree of overlap within corresponding natural product spectra (200-2,000 Da). This informed the decision to create a library of 301 isolates ...
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