With progress in genome sequencing and data sharing, 1000s of bacterial genomes are publicly available. Genome mining – using bioinformatics tools in terms of biosynthetic gene cluster (BGC) identification, analysis and rating – has become a key technology to explore the capabilities for natural product (NP) biosynthesis. Comprehensively, analyzing the genetic potential of the phylum Bacteroidetes revealed Chitinophaga as the most talented genus in terms of BGC abundance and diversity. Guided by the computational predictions, we conducted a metabolomics and bioactivity driven NP discovery program on 25 Chitinophaga strains. High numbers of peerless strain-specific metabolite buckets confirmed the upfront predicted biosynthetic potential and revealed a tremendous uncharted chemical space. Sourcing this dataset, we isolated the new iron chelating nonribosomally-synthesized cyclic tetradeca- and pentadecalipodepsipeptide antibiotics chitinopeptins with activity against Candida , produced by C. eiseniae DSM 22224 and C. flava KCTC 62435, respectively. Teaser: Combination of omics-technologies revealed taxonomical hotspots for specialized metabolites within Bacteroidetes.

Tuberculosis represents one of the ten most common courses of death worldwide and the emergence of multidrug‐resistant M. tuberculosis makes the discovery of novel anti‐tuberculosis active structures an urgent priority. Here, we show that (+)‐floyocidin B representing the first example of a novel dihydroisoquinoline class of fungus‐derived natural products, displays promising antitubercular hit properties. (+)‐Floyocidin B was identified by activity‐guided extract screening and its structure was unambiguously determined by total synthesis. The absolute configuration was deduced from a key synthesis intermediate by single crystal X‐ray diffraction analysis. A hit series was generated by the isolation of further natural congeners and the synthesis of analogs of (+)‐floyocidin B. Extensive biological and physicochemical profiling of this series revealed first structure‐activity relationships and set the basis for further optimization and development of this novel antitubercular scaffold.