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Molecular mechanisms of hypervirulence in antibiotic-resistant Pseudomonas aeruginosa

Award Number: R01AI146425
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: 08/10/2020
PERIOD OF PERFORMANCE END DATE: 07/31/2024

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Molecular mechanisms of hypervirulence in antibiotic-resistant Pseudomonas aeruginosa - PROJECT SUMMARY/ABSTRACT Antibiotic resistance is a major healthcare problem because it renders treatment ineffective, leading to chronic infections and death. Pseudomonas aeruginosa (PSA) is notorious for its capacity to mutate and become antibiotic resistant during chronic infections. Evolutionary theory predicts that these mutations will lead to fitness defects, including decreased growth rates that reduce the resistant organism’s ability to survive competition with wild-type susceptible siblings when antibiotic treatment ends. Moreover, fitness costs could also reduce virulence by reducing the resistant population’s ability to replicate fast enough to overcome killing by the host immune response. In reality, these predictions are frequently contradicted: antibiotic resistant PSA are readily isolated alongside susceptible siblings during decades-long chronic infections, and recently we discovered that antibiotic resistance mutations that increase efflux pump expression can also increase PSA virulence even in the absence of antibiotics. However, the conditions that enable resistant bacteria to compete with susceptible bacteria are unknown and the mechanisms by which resistance mutations increase virulence are unclear. The central hypothesis of this proposal is that mutation of efflux pump components leads to increased virulence in antibiotic resistant strains. The three specific aims of this proposal are to 1) determine the role of quorum sensing in enhanced virulence of aztreonam resistant PSA, 2) determine fitness of aztreonam resistant mutants relative to wild-type PSA, and 3) identify novel therapeutic targets in aztreonam-resistant PSA. In our previous work, both hypervirulent resistant PSA strains had resistance mutations that functioned by increasing mexAB-oprM antibiotic efflux pump expression. In addition to its role exporting antibiotics, MexAB-OprM also secretes a PSA quorum sensing molecule which is involved in regulating several virulence factors. In preliminary experiments, hypervirulent resistant PSA increased swarming and biofilm phenotypes, which are both mediated by the bacterial quorum sensing regulated virulence factor rhamnolipid. In the first aim of this proposal we will test the hypothesis that increased virulence of resistant PSA is due to increased quorum sensing regulated rhamnolipid production. In the second aim, we will test the hypothesis that specific nutrients, stresses, or host cells enable resistant bacteria to compete with susceptible bacteria. In the third aim, we will test the hypothesis that targeted therapies against hypervirulent resistant PSA will reduce virulence and improve clearance during infection, and we will use random transposon mutagenesis in combination with next-generation sequencing to identify new drug targets in antibiotic resistant PSA. These studies will help us understand how antibiotic resistant bacteria can arise during infection, as well as how we can leverage this knowledge and translate it into desperately needed therapies for antibiotic resistant bacteria.


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 = $0 )
2025	2023	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	4	2/18/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $573,835 )
2023	2023	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	4	7/24/2023	NON-COMPETING CONTINUATION	$573,835
														Subtotal = $573,835

Issue Date FY: 2022 ( Subtotal = $573,835 )
2022	2022	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	3	7/19/2022	NON-COMPETING CONTINUATION	$573,835
														Subtotal = $573,835

Issue Date FY: 2021 ( Subtotal = $573,835 )
2021	2021	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	2	7/12/2021	NON-COMPETING CONTINUATION	$573,835
														Subtotal = $573,835

Issue Date FY: 2020 ( Subtotal = $592,360 )
2020	2020	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	1	8/10/2020	NEW	$592,360
														Subtotal = $592,360

Grand Total All Awards = $2,313,865

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Molecular mechanisms of hypervirulence in antibiotic-resistant Pseudomonas aeruginosa

Award Number: R01AI146425

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: 08/10/2020

PERIOD OF PERFORMANCE END DATE: 07/31/2024

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