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Mechanism Of Enterococcus Faecalis Nitro Drug Metabolism And In Vivo Implications

Award Number: R21AI171660
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: 06/03/2022
PERIOD OF PERFORMANCE END DATE: 05/31/2025

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Mechanism Of Enterococcus Faecalis Nitro Drug Metabolism And In Vivo Implications - PROJECT SUMMARY/ABSTRACT Understanding drug metabolism by intestinal microbiota is at the forefront of research to explain why some patients do not adequately respond to therapy. However, there remains a lack of research on infectious diseases and the cellular mechanisms by which specific microbes metabolize antibiotic therapies and its impact on treatment outcomes in patients. To advance this research area, we intend to elucidate how Enterococcus sp. gut bacteria metabolize the nitro-containing drug metronidazole. Enterococcus faecalis and Enterococcus faecium are the main colonizers of the human gut, and also cause opportunistic infections. Metronidazole is an important therapy for Clostridioides difficile infection (CDI), a disease that poses an urgent threat to public health. Furthermore, in CDI patients, colonization of with vancomycin-resistant enterococci (VRE) exacerbates disease severity. E. faecalis, but not E. faecium, degrades metronidazole. Our preliminary data suggests this is due to unique interactions between electrochemical components found in E. faecalis and absent in E. faecium. We will now investigate how this mechanism operates in E. faecalis and the extent to which this bacterium promotes treatment failure for metronidazole. In aim 1 we propose to use microbial genetics and metabolomics to elucidate the mechanism(s) of metronidazole degradation and identify the metabolites formed. Aim 2 will co-culture enterococcal and C. difficile species to identify and measure which species protect C. difficile from being killed by metronidazole. Studies will progress to animals, where we measure the effect of enterococci on metronidazole treatment outcomes and severity of CDI disease. This work will advance knowledge of enterococcal physiology relating to its metabolism and aspects that differentiate E. faecalis from E. faecium. These exploratory studies lay the foundation to understand inter-species interactions between enterococci and C. difficile and how this influences disease development and progression. Public health. E. faecalis, E. faecium and C. difficile are leading pathogens causing diseases in hospitals. This study has significant implications for the diagnosis and treatment of CDI, a disease that imposes a major public health and economic burden in the United States.


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 = -$1,224 )
2026	2023	UNIVERSITY OF TEXAS AT DALLAS	800 WEST CAMPBELL RD.	RICHARDSON	TX	75080	DALLAS	USA	Allergy and Infectious Diseases Research	000	2	2/12/2026	NON-COMPETING CONTINUATION	-$1,224
														Subtotal = -$1,224

Issue Date FY: 2023 ( Subtotal = $232,000 )
2023	2023	UNIVERSITY OF TEXAS AT DALLAS	800 WEST CAMPBELL RD.	RICHARDSON	TX	75080	DALLAS	USA	Allergy and Infectious Diseases Research	000	2	5/19/2023	NON-COMPETING CONTINUATION	$232,000
														Subtotal = $232,000

Issue Date FY: 2022 ( Subtotal = $222,000 )
2022	2022	UNIVERSITY OF TEXAS AT DALLAS	800 W CAMPBELL RD	RICHARDSON	TX	75080	DALLAS	USA	Allergy and Infectious Diseases Research	000	1	6/3/2022	NEW	$222,000
														Subtotal = $222,000

Grand Total All Awards = $452,776

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Mechanism Of Enterococcus Faecalis Nitro Drug Metabolism And In Vivo Implications

Award Number: R21AI171660

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: 06/03/2022

PERIOD OF PERFORMANCE END DATE: 05/31/2025

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