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A team from Rockefeller University has opened a new window into the hidden world of soil microbes, revealing hundreds of previously unknown bacterial genomes and uncovering two promising antibiotic leads. The research, led by Sean F. Brady and published in Nature Biotechnology, tackles a longstanding challenge in microbiology: most bacteria can’t be cultured in the lab, limiting our ability to study and harness them. Since many of our frontline antibiotics were originally derived from microbes, this breakthrough comes at a crucial time as drug resistance continues to rise and antibiotic pipelines thin out.
To access this microbial “dark matter,” the researchers developed a method to extract very large DNA fragments directly from soil and sequence them using advanced long-read nanopore technology. This approach allowed them to assemble complete genomes with much greater confidence and detail. They then applied a synthetic bioinformatic natural products (synBNP) method to predict the chemical structures of molecules encoded in the genomes and synthesize them in the lab. This strategy successfully turned hidden genetic blueprints into real compounds.
From a single forest soil sample, the team pieced together hundreds of never-before-seen genomes, representing more than 99% entirely new bacterial species. Among the natural products uncovered were two powerful antibiotic candidates: erutacidin, which disrupts bacterial membranes through a novel mechanism, and trigintamicin, which targets ClpX, a rare antibacterial pathway. Both show promise against highly drug-resistant bacteria, highlighting soil’s potential as a wellspring of new medicines.
Beyond drug discovery, this approach has wide implications for ecology, agriculture, and climate science, as soil bacteria also play vital roles in shaping ecosystems. Brady and colleagues describe this work as just the “tip of the spear”—a scalable method that could revolutionize our ability to tap into microbial diversity and unlock new therapeutics at a time when they are urgently needed.
