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Cell envelope stress responses and the mechanism of antibiotic tolerance in Gram-negative pathogens

Award Number: R01AI143704
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Cell envelope stress responses and the mechanism of antibiotic tolerance in Gram-negative pathogens - Project Summary Bacteria often resist killing by normally bactericidal antibiotics, resulting in clinical treatment failure and the development of antibiotic resistance. The ability to survive damage elicited by exposure to antibiotics is termed tolerance. Tolerance is likely responsible for the recurrence of infections after discontinuation of antimicrobial therapy, and provides a reservoir of a bacterial population that can develop full scale resistance. An extreme case of tolerance is the formation of persister cells, which do not experience antibiotic-induced damage due to dormancy. However, we and others have found that many Gram-negative pathogens (Vibrio cholerae, Pseudomonas aeruginosa, Enterobacter cloacae, Haemophilus influenzae and Acinetobacter baumannii) are fully susceptible to damage induced by cell wall acting antibiotics (beta lactams), but yet survive at very high levels. Survival is enabled through the formation of viable spheres that are devoid of detectable cell wall material and that recover to normal shape upon withdrawal of the antibiotic. In our model organism, the cholera pathogen V. cholerae, tolerance is promoted by cell envelope stress responses, especially the two-component system WigKR. WigKR is induced by cell wall acting antibiotics and mounts a complex response that ultimately enables recovery from the spherical state. This response includes upregulation of cell wall synthesis functions, outer membrane synthesis, phospholipid synthesis and downregulation of motility and iron acquisition genes. How this response promotes tolerance is poorly understood, and so are the mechanisms of tolerance in other Gram-negative bacteria. Here, we aim to interrogate V. cholerae's cell envelope stress responses and their relationship with beta lactam tolerance and post-antibiotic recovery. Using genetic and biochemical approaches, we will find the elusive induction signal sensed by the histidine kinase WigK. Leveraging extensive datasets comprehensively describing the WigKR regulon, we will measure each individual regulon member's contribution to beta lactam tolerance. Lastly, we will apply what we have learned in the V. cholerae model to other Gram-negative pathogens exhibiting high beta lactam tolerance, specifically E. cloacae and P. aeruginosa. Our experiments will yield novel insight into the mechanisms of antibiotic tolerance and result in the identification of candidate drug targets for anti-tolerance adjuvants of beta lactams.


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 = $0 )
2024	2023	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Allergy and Infectious Diseases Research	000	5	8/7/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $391,587 )
2023	2023	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Allergy and Infectious Diseases Research	000	5	12/2/2022	NON-COMPETING CONTINUATION	$391,587
														Subtotal = $391,587

Issue Date FY: 2022 ( Subtotal = $391,965 )
2022	2022	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Allergy and Infectious Diseases Research	000	4	12/21/2021	NON-COMPETING CONTINUATION	$391,965
														Subtotal = $391,965

Issue Date FY: 2021 ( Subtotal = $392,315 )
2021	2021	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Allergy and Infectious Diseases Research	000	3	12/25/2020	NON-COMPETING CONTINUATION	$392,315
														Subtotal = $392,315

Issue Date FY: 2020 ( Subtotal = $392,639 )
2020	2020	CORNELL UNIVERSITY, INC	373 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Allergy and Infectious Diseases Research	000	2	12/31/2019	NON-COMPETING CONTINUATION	$392,639
														Subtotal = $392,639

Issue Date FY: 2019 ( Subtotal = $392,939 )
2019	2019	CORNELL UNIVERSITY, INC	373 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Allergy and Infectious Diseases Research	000	1	1/10/2019	NEW	$392,939
														Subtotal = $392,939

Grand Total All Awards = $1,961,445

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Cell envelope stress responses and the mechanism of antibiotic tolerance in Gram-negative pathogens

Award Number: R01AI143704

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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