Abstract
The growing problem of antibiotic resistance has led to the exploration of uncultured bacteria as potential sources of new antimicrobials. PCR amplicon analyses and short-read sequencing studies of samples from different environments have reported evidence of high biosynthetic gene cluster (BGC) diversity in metagenomes, indicating their potential for producing novel and useful compounds. However, recovering full-length BGC sequences from uncultivated bacteria remains a challenge due to the technological restraints of short-read sequencing, thus making assessment of BGC diversity difficult. Here, long-read sequencing and genome mining were used to recover >1400 mostly full-length BGCs that demonstrate the rich diversity of BGCs from uncultivated lineages present in soil from Mars Oasis, Antarctica. A large number of highly divergent BGCs were not only found in the phyla Acidobacteriota, Verrucomicrobiota and Gemmatimonadota but also in the actinobacterial classes Acidimicrobiia and Thermoleophilia and the gammaproteobacterial order UBA7966. The latter furthermore contained a potential novel family of RiPPs. Our findings underline the biosynthetic potential of underexplored phyla as well as unexplored lineages within seemingly well-studied producer phyla. They also showcase long-read metagenomic sequencing as a promising way to access the untapped genetic reservoir of specialised metabolite gene clusters of the uncultured majority of microbes.
Highlights
Throughout the last century, bacterial natural products have proven invaluable for humankind
To assess the advantages of long-read sequencing for biosynthetic gene cluster (BGC) detection and classification, the output was compared with BiosyntheticSPAdes, which allows the assembly of nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) from short-read sequences by following an ambiguous assembly graph using a priori information about their modularity
Metagenomics reveal biosynthetic potential of underexplored bacterial lineages In our dataset, we found a large number of BGCs in underexplored phyla not usually associated with specialised metabolites
Summary
Throughout the last century, bacterial natural products have proven invaluable for humankind. Their diversity has been harnessed to treat different ailments, and above all, to fight infectious disease. First efforts to characterise and harness the specialised metabolite diversity encoded in metagenomes have shown promising results [2,3,4]. Metagenomic library screenings have yielded novel compounds, among them antibiotics [3, 5, 6], while sequence-based studies have documented their diversity. Finding efficient ways to access this treasure trove of diverse and unexplored specialised metabolites will expand our understanding of microbial natural products, yield novel and useful compounds, and be an important step towards the development of much-needed antimicrobials
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