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Genetic Factors associated with phenotypic beta-lactam resistance in extended-spectrum beta lactamase-producing Enterobacterales

Award Number: R01AI175414
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Genetic Factors associated with phenotypic beta-lactam resistance in extended-spectrum beta lactamase-producing Enterobacterales - PROJECT SUMMARY/ABSTRACT Extended-spectrum beta-lactamase (ESBL)-producing Enterobacterales (ESBL-PE) have become widespread in recent years, posing a serious threat to the treatment of common bacterial infections. Increased use of last resort carbapenem antibiotics to treat ESBL-PE infections has fueled the emergence of carbapenem-resistant Enterobacterales. Whole genome sequencing (WGS)-based prediction of antibiotic resistance phenotypes may enable early initiation of appropriate treatment options for ESBL-PE infections, including selection of carbapenem-sparing beta-lactam regimens. However, existing genomic prediction models have had relatively poor accuracy for predicting resistance to beta-lactams in ESBL-PE. The genetic environment of ESBL genes, including their location in the bacterial genome and association with mobile genetic elements (MGEs), is unaccounted for in these models. These structural factors may contribute to beta-lactam resistance by providing promotors modulating the expression of ESBL genes and enabling their duplication and mobilization within and between Gram-negative bacteria. We hypothesize that including MGEs in genomic prediction models will improve detection of beta-lactam resistance phenotypes in ESBL-PE. The objectives of this proposal are to 1) determine how MGEs modulate beta-lactam minimum inhibitory concentrations (MICs) in ESBL-PE and 2) develop and optimize multivariate regression models for predicting beta-lactam resistance from WGS data in ESBL-PE. Our multidisciplinary research team has the necessary expertise in bacterial genomics, molecular biology, infectious diseases epidemiology, and biostatistics to ensure successful completion of the proposed studies. To characterize the genetic environment of ESBL genes, we will take advantage of the ability of nanopore WGS to resolve structurally complex genomic regions including MGEs and plasmids. We will test our hypothesis through the following three aims: 1) we will comprehensively genotype and phenotype a large collection of clinical ESBL-PE isolates (n=450) to test the association between specific MGE genotypes and beta-lactam MICs; 2) we will evaluate potential mechanisms whereby MGEs may affect beta-lactam resistance phenotypes, focusing on the role that MGE-associated promotors play in modulating ESBL gene expression and the impact of ESBL gene copy number on beta-lactam MICs; 3) we will use machine learning to build and optimize multivariate regression models incorporating MGE genotypes and other genetic factors to predict beta- lactam resistance phenotypes and validate our resulting models in a prospective collection of 200 ESBL-PE isolated from urine cultures. The development of rapid diagnostic methods that predict antibiotic treatment options to ESBL-PE should be a research priority. In addition to determining how MGEs contribute to ESBL-PE resistance phenotypes, the proposed research will help enable integration of nanopore WGS into surveillance and diagnostic approaches to detect beta-lactam resistance in ESBL-PE and facilitate the selection of appropriate carbapenem-sparing regimens for ESBL-PE infections using genomic prediction models.


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 = $473,714 )
2025	2025	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Allergy and Infectious Diseases Research	001	2	11/13/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$473,714
2025	2025	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Allergy and Infectious Diseases Research	003	2	3/25/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$217,508
2025	2024	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Allergy and Infectious Diseases Research	002	1	3/25/2025	NEW	-$217,508
2025	2024	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Allergy and Infectious Diseases Research	000	1	11/13/2024	NEW	$0
														Subtotal = $473,714

Issue Date FY: 2024 ( Subtotal = $436,766 )
2024	2024	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Allergy and Infectious Diseases Research	000	1	12/15/2023	NEW	$393,091
2024	2024	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Allergy and Infectious Diseases Research	001	1	6/6/2024	NEW	$43,675
														Subtotal = $436,766

Grand Total All Awards = $910,480

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Genetic Factors associated with phenotypic beta-lactam resistance in extended-spectrum beta lactamase-producing Enterobacterales

Award Number: R01AI175414

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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