Biosynthetic novelty index reveals the metabolic potential of rare actinobacteria isolated from highly oligotrophic sediments

Abstract

Calculations predict that testing of 5 000-10 000 molecules and 1 billion US dollars (£0.8 billion, £1=$1.2) are required for one single drug to come to the market. A solution to this problem is to establish more efficient protocols that reduce the high rate of re-isolation and continuous rediscovery of natural products during early stages of the drug development process. The study of ‘rare actinobacteria’ has emerged as a possible approach for increasing the discovery rate of drug leads from natural sources. Here, we define a simple genomic metric, defined as biosynthetic novelty index (BiNI), that can be used to rapidly rank strains according to the novelty of the subset of encoding biosynthetic clusters. By comparing a subset of high-quality genomes from strains of different taxonomic and ecological backgrounds, we used the BiNI score to support the notion that rare actinobacteria encode more biosynthetic gene cluster (BGC) novelty. In addition, we present the isolation and genomic characterization, focused on specialized metabolites and phenotypic screening, of two isolates belonging to genera Lentzea and Actinokineospora from a highly oligotrophic environment. Our results show that both strains harbour a unique subset of BGCs compared to other members of the genera Lentzea and Actinokineospora. These BGCs are responsible for potent antimicrobial and cytotoxic bioactivity. The experimental data and analysis presented in this study contribute to the knowledge of genome mining analysis in rare actinobacteria and, most importantly, can serve to direct sampling efforts to accelerate early stages of the drug discovery pipeline.