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The LiaFSR system and antimicrobial peptide resistance in enterococci

Award Number: R01AI134637
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: 05/18/2018
PERIOD OF PERFORMANCE END DATE: 04/30/2031

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The LiaFSR system and antimicrobial peptide resistance in enterococci - Vancomycin-resistant enterococci (VRE) are one of the most challenging organisms in clinical settings. Indeed, in 2019, enterococci (Enterococcus faecalis and E. faecium) were responsible for approximately 400,000 deaths worldwide, most of them directly attributable to antimicrobial resistance. Further, vancomycin-resistant Enterococcus faecium and E. faecalis are among the costliest (ca. $539 M/year) among healthcare-associated infections and cause increased morbidity and mortality, particularly in critically ill patients. Daptomycin (DAP), a cell membrane-targeting lipopeptide antibiotic with potent activity against VRE, has become a key “front-line” antimicrobial agent against these organisms. However, development of resistance during therapy is a daunting challenge. Our group was the first to identify the genetic and biochemical bases of DAP and antimicrobial peptide (AMP) resistance. During the first period of this project, we identified that the major mediator of DAP resistance in enterococci is a four-component system (designated LiaFSRX) involved in orchestrating the cell envelope adaptive response to antibiotics and AMPs. We discovered a novel protein, LiaX, which is a surface exposed peptide functioning as the main orchestrator of the LiaFSR-mediated response by orchestrating cell membrane phospholipid remodeling (a phenotype associated with DAP resistance). Additionally, LiaX functions as a sensor and sentinel molecule to maintain the cell envelope response. We also provide evidence that LiaX is involved in the seesaw effect (hypersusceptibility to β-lactams upon development of DAP resistance) and interacts with penicillin-binding protein (PBP) 4 (a key enterococcal enzyme required for cell-wall synthesis in the presence of β-lactams). Further, the molecular basis of the LiaX-mediated phospholipid remodeling during the DAP “attack” involves another novel protein (LiaY, also discovered by our group) that, in conjunction with cardiolipin synthases (Cls), are responsible for the changes in phospholipid architecture associated with DAP resistance. Here, we will focus on the detailed characterization of LiaX and LiaY under the overall hypotheses that i) characterization of LiaX and LiaY in cell membrane function and peptidoglycan synthesis is likely to uncover specific cell envelope pathways that can be manipulated therapeutically and, ii) targeting LiaX with an immunologic approach is feasible to prevent and manage difficult to treat enterococcal infections. We have developed a comprehensive experimental approach in three major specific aims. In Sp. Aim I, we will dissect the molecular basis of LiaX processing and interactions with PBP-4. Specific Aim II will focus on evaluating immunization and immunotherapy against LiaX to resensitize enterococci to DAP using a model of murine endocarditis. Specific Aim III will characterize the molecular basis of Cls and LiaY interactions and how they affect membrane adaptation. Our proposal is likely to uncover new molecular and biochemical details of the function of LiaFSRX as a novel cell envelope system with a distinct biological paradigm. The project will also provide the basis to use an unprecedented vaccine and monoclonal antibodies against MDR enterococci.


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 = $806,820 )
2026	2026	THE METHODIST HOSPITAL RESEARCH INSTITUTE	6565 FANNIN ST STE D200	HOUSTON	TX	77030	HARRIS	USA	Allergy and Infectious Diseases Research	000	7	5/20/2026	COMPETING CONTINUATION	$806,820
														Subtotal = $806,820

Issue Date FY: 2025 ( Subtotal = -$32,121 )
2025	2022	THE METHODIST HOSPITAL RESEARCH INSTITUTE	6565 FANNIN ST STE D200	HOUSTON	TX	77030	HARRIS	USA	Allergy and Infectious Diseases Research	000	6	2/25/2025	NON-COMPETING CONTINUATION	-$32,121
														Subtotal = -$32,121

Issue Date FY: 2022 ( Subtotal = $489,288 )
2022	2022	METHODIST HOSPITAL, THE	6670 BERTNER AVE	HOUSTON	TX	77030	HARRIS	USA	Allergy and Infectious Diseases Research	005	6	9/14/2022	NON-COMPETING CONTINUATION	$226,259
2022	2022	METHODIST HOSPITAL, THE	6670 BERTNER AVE	HOUSTON	TX	77030	HARRIS	USA	Allergy and Infectious Diseases Research	002	6	6/22/2022	NON-COMPETING CONTINUATION	$489,288
2022	2021	METHODIST HOSPITAL, THE	6670 BERTNER AVE	HOUSTON	TX	77030	HARRIS	USA	Allergy and Infectious Diseases Research	001	5	3/15/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$454,282
2022	2021	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Allergy and Infectious Diseases Research	004	4	9/14/2022	NON-COMPETING CONTINUATION	-$33,998
2022	2021	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Allergy and Infectious Diseases Research	000	4	3/15/2022	NON-COMPETING CONTINUATION	-$454,282
2022	2020	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Allergy and Infectious Diseases Research	003	3	9/14/2022	NON-COMPETING CONTINUATION	-$192,261
														Subtotal = $489,288

Issue Date FY: 2021 ( Subtotal = $488,280 )
2021	2021	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Allergy and Infectious Diseases Research	000	4	6/30/2021	NON-COMPETING CONTINUATION	$488,280
														Subtotal = $488,280

Issue Date FY: 2020 ( Subtotal = $641,586 )
2020	2020	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Allergy and Infectious Diseases Research	000	3	6/12/2020	NON-COMPETING CONTINUATION	$641,586
														Subtotal = $641,586

Issue Date FY: 2019 ( Subtotal = $643,198 )
2019	2019	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Allergy and Infectious Diseases Research	000	2	5/27/2019	NON-COMPETING CONTINUATION	$643,198
														Subtotal = $643,198

Issue Date FY: 2018 ( Subtotal = $658,280 )
2018	2018	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Allergy and Infectious Diseases Research	001	1	7/6/2018	NEW	$0
2018	2018	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Allergy and Infectious Diseases Research	000	1	5/18/2018	NEW	$658,280
														Subtotal = $658,280

Grand Total All Awards = $3,695,331

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The LiaFSR system and antimicrobial peptide resistance in enterococci

Award Number: R01AI134637

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: 05/18/2018

PERIOD OF PERFORMANCE END DATE: 04/30/2031

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