Wednesday, April 24, 2024 4/24/2024

Role and regulation of a peptidoglycan synthesis enzyme required for cephalosporin resistance in enterococci

Award Number: F31AI156980
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

Group Awards By Issue Date FY or Funding FY:

View Award Abstract

PROJECT SUMMARY/ABSTRACT: Infective endocarditis, a condition in which bacteria grow in a biofilm-like state on the valves of the heart, is a deadly complication of bloodstream infections. Enterococcus species are responsible for 30% of healthcare- acquired endocarditis. When caused by multi-drug resistant strains, such as vancomycin-resistant enterococci (VRE), infective endocarditis is nearly untreatable and uniformly fatal. The CDC considers VRE a serious threat and estimates 5,400 VRE-related deaths and over $500 million in associated healthcare costs in 2017. A major risk factor for the development of enterococcal endocarditis and other infections is prior treatment with cephalosporin antibiotics. The two most clinically relevant species of Enterococcus, E. faecalis and E. faecium, are intrinsically resistant to cephalosporins. Treatment with cephalosporin antibiotics allows commensal enterococci to proliferate and disseminate to the bloodstream, a prerequisite for infection of the heart valves. The goal of this project is to further our understanding of molecular mechanisms of cephalosporin resistance in enterococci. This understanding will enable development of new therapies that both reduce the occurrence of enterococcal infections and improve treatment options to overcome recalcitrant endocardial infections. Specifically, a novel link will be investigated between two known cephalosporin resistance determinants, IreK and MurAA. IreK is a kinase that is thought to sense and respond to cell wall stress, including that caused by inhibition of peptidoglycan crosslinking upon cephalosporin treatment. However, the targets of IreK signaling that facilitate this response, and ultimately cephalosporin resistance, are largely unknown. MurAA, an enzyme that catalyzes the first committed step in peptidoglycan synthesis is also required for cephalosporin resistance. The central hypothesis of this project is that MurAA is a downstream target of IreK signaling, such that regulation of MurAA is one mechanism by which IreK controls cephalosporin resistance. Preliminary evidence suggests that this regulation is mediated by the known IreK-phosphorylation substrate, IreB. This hypothesis will be addressed in two aims. Aim 1 will determine how IreB and IreK signaling impact functions of MurAA. Aim 2 will identify MurAA interaction partners and determine the functional consequences of these interactions. Preliminary data suggest that a protein-protein interaction is important for either facilitating or regulating functions of MurAA. This work will be conducted at the Medical College of WI under the sponsorship of Dr. Christopher Kristich. The sponsor and institution are well-equipped to provide resources and support for this fellowship. In collaboration with the sponsor, the candidate has designed a training plan that complements this project. The training plan supports development of broad technical, communication and mentoring skills and encourages the professional development of the candidate. Development of these competencies will catalyze a successful career for the candidate as a well-rounded, independent scientist investigating microbes in human health and disease.


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: 2024 ( Subtotal = -$4,577 )
2024	2022	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Allergy and Infectious Diseases Research	000	2	10/31/2023	NON-COMPETING CONTINUATION	-$4,577
														Subtotal = -$4,577

Issue Date FY: 2022 ( Subtotal = $46,752 )
2022	2022	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Allergy and Infectious Diseases Research	002	2	5/27/2022	NON-COMPETING CONTINUATION	-$1
2022	2022	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Allergy and Infectious Diseases Research	001	2	5/12/2022	NON-COMPETING CONTINUATION	$717
2022	2022	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Allergy and Infectious Diseases Research	000	2	12/17/2021	NON-COMPETING CONTINUATION	$46,036
														Subtotal = $46,752

Issue Date FY: 2021 ( Subtotal = $46,036 )
2021	2021	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Allergy and Infectious Diseases Research	001	1	1/11/2021	NEW	$0
2021	2021	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Allergy and Infectious Diseases Research	000	1	11/23/2020	NEW	$45,520
2021	2021	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Allergy and Infectious Diseases Research	002	1	2/8/2021	NEW	$516
														Subtotal = $46,036

Grand Total All Awards = $88,211

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Role and regulation of a peptidoglycan synthesis enzyme required for cephalosporin resistance in enterococci

Award Number: F31AI156980

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer