From caffeine jolts to lifesaving antibiotics like penicillin, natural products are deeply woven into the fabric of modern life. Yet thousands of potential bioactive compounds remain undiscovered, obscured by their complexity or the tiny amounts produced naturally. To crack this biological treasure chest wide open, scientists at the University of Illinois Urbana-Champaign have devised a new, hyper-efficient system called FAST-NPS—Fast-Track Automated Screening Technology for Natural Product Synthesis—to rapidly find and scale up these elusive compounds, particularly in the bacteria genus Streptomyces. Findings from the new study were published recently in Cell Systems. 

Nature excels where chemists struggle. Microorganisms produce highly complex, structurally diverse natural products through intricate enzyme pathways. These pathways are typically encoded by clusters of genes, known as biosynthetic gene clusters (BGCs). While modern genomic sequencing and bioinformatics tools have made it easier to pinpoint these BGCs, the challenge remains to identify which clusters actually yield valuable bioactive products. This is compounded by the fact that useful compounds often exist only in minuscule quantities, nearly impossible to detect without specialized techniques.

Genes That Shield, Genes That Reveal

Enter FAST-NPS, an automated and scalable platform developed by researchers under the guidance of Huimin Zhao, the Steven L. Miller Chair of Chemical and Biomolecular Engineering. Zhao’s team harnessed "self-resistance genes"—genes microorganisms naturally evolve to protect themselves from their own potentially harmful compounds. These genes, positioned within the same clusters, act as reliable indicators of bioactivity.

“We are using the self-resistance genes as markers to prioritize BGCs of natural products with bioactivity,” explained Yujie Yuan, the lead researcher behind the study. By focusing on these markers, the researchers streamlined their search, significantly enhancing discovery efficiency by narrowing down promising candidates early in the process.

Once the team identifies a promising gene cluster using the Antibiotic Resistant Target Seeker tool (ARTS), they use a high-efficiency direct cloning method called CAPTURE to transfer these clusters into bacterial hosts capable of synthesizing the desired compounds. Although CAPTURE was effective, Zhao admitted the process was "tedious and involves a lot of manual work.” Automation was the next logical step.

Automating Nature’s Drug Lab

Integrating their cloning and expression methods into the Illinois Biological Foundry for Advanced Biomanufacturing (iBioFAB), Zhao and his team fully automated FAST-NPS. Tasks like PCR amplification, RNA transcription, bacterial transformation, and compound synthesis—once painstakingly manual—now happen seamlessly, allowing the parallel processing of hundreds of gene clusters simultaneously. What previously took a month to accomplish for just ten clusters can now scale to hundreds, dramatically accelerating the discovery cycle.

“We spent a lot of time and effort to develop the automation workflow,” Yuan reflected. “This was a big challenge because we had to develop each component, from PCR and RNA transcription to bacterial transformation and heterologous expression. I am very proud of our CAPTURE method and am excited to report this more powerful version for the discovery of bioactive compounds.”

Early tests have been impressive. FAST-NPS demonstrated a remarkable 95% success rate, cloning 105 gene clusters from 11 Streptomyces strains. Five of these clusters produced promising bioactive compounds, proving the method’s potency. However, Zhao points out that hurdles remain. Out of more than 100 cloned clusters, only 12 successfully expressed functional compounds. "We still need to improve the success rate of heterologous expression,” Zhao acknowledged. “This is a challenge that we will try to address."

For now, FAST-NPS marks a transformative leap forward, automating and scaling the search for new natural products—and promising to unleash nature’s hidden pharmaceuticals more rapidly than ever before.