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Triple-enriched metagenomics for robust resistome analysis

Award Number: R01AI173928
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/15/2024
PERIOD OF PERFORMANCE END DATE: 02/28/2029

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Triple-enriched metagenomics for robust resistome analysis - Project Summary: Despite reductions in antimicrobial use and implementation of antibiotic stewardship programs, antimicrobial resistant (AMR) pathogens continue to emerge and persist, causing millions of deaths every year. The long-term goal of this proposal is to decrease clinical AMR incidence by advancing knowledge of how AMR develops, persists and transmits to pathogens within the microbiome. The overall objective of this project is to develop a novel high-throughput method for generating enriched long-read sequencing data that accurately reflects the in situ dynamics of AMR genes across entire microbial communities. This is a major gap in methodology that hampers knowledge discovery and leads to suboptimal patient outcomes. The rationale is that this method will enable fundamental advances in both applied and basic research through: improved prediction about when and how bacteria exchange AMR genes; and rapid, lower-cost, higher-throughput generation of metagenomic resistome data. The project objective is achieved through three specific aims: 1) Increase the sensitivity and specificity of probe-based pre-sequencing enrichment; 2) Generate contextualized metagenomic sequence data with real-time enrichment of antimicrobial resistance genes; and 3) Evaluate the performance of triple-enrichment using samples with diverse antimicrobial resistance gene composition. Under aim 1, probes for all potential off- target (i.e., AMR) DNA will be designed using a novel compressed colored de Bruijn graph. Probes will be manufactured and used to deplete off-target DNA from metagenomic samples prior to enrichment of AMR genes. For aim 2, adaptive Nanopore sequencing will perform real-time rejection of off-target DNA using a compressed pangenomic index of all off-target regions, followed by on-the-fly classification of antimicrobial resistance genes. For aim 3, the potential bias of probe- and sequence-based enrichment will be quantified on a gene-by-gene basis to fully evaluate the performance of the enrichment workflow for various sample types and use cases. The proposed research is innovative for two major reasons: first, it enables the applied use of microbial ecology for clinical and public health applications, which is a major gap in the field of metagenomics; second, it allows for deep sequencing and robust genomic co-localization of rare and low-abundance metagenomic targets, which is currently very difficult to obtain. The proposed methodology will open new horizons for basic research into how and why bacterial communities evolve; and under what conditions diverse bacteria share critical functions such as AMR. The proposed research is significant because it will have broad applicability to many critical activities for combating AMR, including patient-centric decisions about antibiotic use and public health activities such as AMR surveillance. The proposed advancements will help predict AMR emergence events in patients and populations; identify hot-spots of AMR development and dissemination in hospitals and the community; and help track critically important AMR genes that may be rare or low-abundance within a given environment or set of samples.


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: 2025 ( Subtotal = $411,930 )
2025	2025	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Allergy and Infectious Diseases Research	003	2	8/15/2025	NON-COMPETING CONTINUATION	$748,594
2025	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Allergy and Infectious Diseases Research	001	1	7/1/2025	TERMINATION	-$336,664
2025	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Allergy and Infectious Diseases Research	002	1	7/9/2025	OTHER REVISION	$0
2025	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Allergy and Infectious Diseases Research	000	1	4/18/2025	TERMINATION	$0
														Subtotal = $411,930

Issue Date FY: 2024 ( Subtotal = $728,432 )
2024	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Allergy and Infectious Diseases Research	001	1	5/31/2024	NEW	$0
2024	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Allergy and Infectious Diseases Research	000	1	4/15/2024	NEW	$728,432
														Subtotal = $728,432

Grand Total All Awards = $1,140,362

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Triple-enriched metagenomics for robust resistome analysis

Award Number: R01AI173928

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/15/2024

PERIOD OF PERFORMANCE END DATE: 02/28/2029

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