Metagenomic study of lake microbial mats reveals protease-inhibiting antiviral peptides from a core microbiome member

In contrast to the large body of work on bioactive natural products from individually cultivated bacteria, the chemistry of environmental microbial communities remains largely elusive. Here, we present a comprehensive bioinformatic and functional study on a complex and interaction-rich ecosystem, algal-bacterial (microbial) mats of Lake Chilika in India, Asia's largest brackish water body. We report the bacterial compositional dynamics over the mat life cycle, >1,300 reconstructed environmental genomes harboring >2,200 biosynthetic gene clusters (BGCs), the successful cultivation of a widespread core microbiome member belonging to the genus , heterologous reconstitution of two silent biosynthetic pathways, and new compounds with potent protease inhibitory and antiviral activities. The identified substances, posttranslationally modified peptides from the graspetide and spliceotide families, were targeted among the large BGC diversity by applying a strategy focusing on recurring multi-BGC loci identified in diverse samples, suggesting their presence in successful colonizers. In addition to providing broad insights into the biosynthetic potential of a poorly studied community from sampling to bioactive substances, the study highlights the potential of ribosomally synthesized and posttranslationally modified peptides as a large, underexplored resource for antiviral drug discovery.