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Development of ClusterBuild to Synthesize Biosynthetic Gene Clusters

Award Number: R43GM163471
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/02/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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Development of ClusterBuild to Synthesize Biosynthetic Gene Clusters - Project Summary/Abstract Development of ClusterBuild to Synthesize Biosynthetic Gene Clusters Opportunity Number: PA-24-245 PIs: Christopher L. Warren and Mary S. Ozers The ability to synthesize large biosynthetic gene clusters (BGCs) is essential for unlocking the therapeutic potential of natural products, including next-generation antibiotics. Many promising BGCs are derived from unculturable microbes, making direct access to their DNA challenging. Existing methods for assembling large constructs, such as PCR assembly, Golden Gate cloning, and solid-phase synthesis, are prohibitively expensive, labor-intensive, and slow when scaled beyond 10 kb, presenting a critical bottleneck in natural product discovery. These limitations hinder broader participation in synthetic biology and delay translation from genomic data to biomedical applications. This project proposes ClusterBuild, a novel platform that enables cost-effective, high-fidelity synthesis of large DNA constructs (up to 100 kb) by combining DNA microarrays with peptide nucleic acid (PNA)-based error correction and isothermal assembly. PNAs can be used to correct DNA synthesis errors due to their high binding affinity and specificity for complementary DNA sequences, enabling them to selectively hybridize to mismatched regions and facilitate targeted removal of erroneous DNA strands. ClusterBuild leverages high-density photolithographic microarrays to generate massive oligo libraries, while complementary PNA arrays are used to selectively purify error-free sequences. Aim 1 will demonstrate that PNA microarrays can purify high-fidelity oligonucleotides generated from a commercial DNA microarray using sequence-specific melting temperature (Tm) elution. Aim 2 will verify that purified DNA oligos can be efficiently assembled into a 12 kb biosynthetic gene cluster using barcoded, overlapping oligonucleotides and multi-stage isothermal assembly. Aim 3 will confirm functional expression of the assembled cluster in E. coli to produce a class II lanthipeptide, a promising compound with low micromolar activity against the pathogen Klebsiella pneumoniae. In Phase II, the full end-to-end workflow will be implemented using a digital micromirror device (DMD)-based microarray synthesizer to scale synthesis up to 100 megabases. The ClusterBuild technology will offer three key advantages over commercially available options by achieving more than 100-fold cost savings, a 50-fold increase in construct length, and fewer errors of one per 10 kb length. This proposal supports the Build step in the Design-Build-Test-Learn cycle, unlocking broader participation in synthetic biology and natural product drug discovery.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $306,151 )
2026	2026	PROTEOVISTA LLC	510 CHARMANY DR STE 57	MADISON	WI	53719	DANE	USA	Biomedical Research and Research Training	000	1	6/5/2026	NEW	$306,151
														Subtotal = $306,151

Grand Total All Awards = $306,151

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Development of ClusterBuild to Synthesize Biosynthetic Gene Clusters

Award Number: R43GM163471

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 06/02/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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