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Reverse Engineering High Yield Lasso Peptide Production by a Burkholderia Heterologous Host

Award Number: F31GM150250
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 01/16/2024
PERIOD OF PERFORMANCE END DATE: 01/15/2025

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Reverse Engineering High Yield Lasso Peptide Production by a Burkholderia Heterologous Host - ABSTRACT Lasso peptides are bacterial metabolites characterized by a unique knotted configuration that confers thermal stability, proteolytic resistance, and potent target affinity in biological applications. Known lasso peptides have a diversity of biological functions, including as antibiotics. In terms of modification for drug development, they are recognized for their ability to be engineered via epitope grafting and genetically encoded libraries. However, the lack of a viable platform to produce lasso peptides has hindered the discovery and development of lasso-based drug leads. Chemical synthesis of lasso peptides is impeded by the lasso fold, positioning microbial production as a favorable alternative. However, heterologous expression of lasso peptide gene clusters (most commonly using E. coli as the bacterial host) results in low yield (<15 mg/L). In an experiment to test the expression of the model lasso peptide capistruin in an alternative Burkholderia bacterial host, a stochastic overproducer clone was identified. Preliminary investigation into the underlying molecular mechanisms of capistruin overproduction led to the recapitulation of high yield capistruin production (up to 130%) by way of plasmid copy number modulation. Production of capistruin with this alternative Burkholderia host corresponds to a yield 800-fold greater than that reported for production using E. coli. Our production platform was validated when Burkholderia was employed to express an orphan gene cluster from the endosymbiont Mycetohabitans sp. B13 (Burkholderiaceae), leading to the discovery of two lasso peptides. The objectives of this proposal are to further establish an effective production platform for novel lasso peptides while simultaneously deepening our understanding of the molecular determinants of compound overproduction by the Burkholderia host.


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 = $0 )
2026	2024	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Biomedical Research and Research Training	000	1	1/27/2026	NEW	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $48,974 )
2024	2024	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Biomedical Research and Research Training	002	1	6/11/2024	NEW	$1,280
2024	2024	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Biomedical Research and Research Training	001	1	1/10/2024	NEW	$0
2024	2024	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Biomedical Research and Research Training	000	1	1/10/2024	NEW	$47,694
														Subtotal = $48,974

Grand Total All Awards = $48,974

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Reverse Engineering High Yield Lasso Peptide Production by a Burkholderia Heterologous Host

Award Number: F31GM150250

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 01/16/2024

PERIOD OF PERFORMANCE END DATE: 01/15/2025

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