A Genomic Screening Approach to the Structure-Guided Identification of Drug Candidates from Natural Sources

The potential of actinomycetes to produce natural products has been exploited for decades. Recent genomic sequence analyses have revealed a previously unrecognized biosynthetic potential and diversity. In order to rationally exploit this potential, we have developed a sequence‐guided genetic screening strategy. In this “genome mining” approach, genes that encode tailoring enzymes from natural product biosyntheses pathways serve as indicator genes for the identification of strains that have the genetic potential to produce natural products of interest. We chose halogenases, which are known to be involved in the synthesis of halometabolites as representative examples. From PCR screening of 550 randomly selected actinomycetes strains, we identified 103 novel putative halogenase genes. A phylogenetic analysis of the corresponding putative halogenases, and the determination of their sequential context with mass spectrometric analysis of cultures filtrates revealed a distinct correlation between the sequence and secondary metabolite class of the halometabolite. The described screening strategy allows rapid access to novel natural products with predetermined structural properties. Novel drugs from known strains. A PCR‐based screening strategy that targets genes involved in the tailoring of metabolites can be used as a tool for the efficient preselection of microorganisms that produce structurally predetermined drug candidates. As a proof of concept, the application of halogenases as marker genes led to the exact prediction and identification of the novel chlorinated xanthone antibiotic CBS40, which displays broad antibacterial activity.