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Exploiting Riboswitch Sensors to Reveal Antibiotics Uptake and Retention in Gram Negative Bacteria

Award Number: R01AI136794
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

Group Awards By Issue Date FY or Funding FY:

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ABSTRACT Infections caused by MDR Pseudomonas aeruginosa and other Gram-negative pathogens challenge clinicians to find safe and effective antibiotic regimens that can eradicate these opportunistic pathogens from the frail, often immunocompromised hosts that they target. Two features of the P. aeruginosa cell envelope - its limited permeability to small molecules and the large number of both constitutive and inducible efflux systems it contains - render this pathogen intrinsically resistant to many available antimicrobials and contribute to acquired resistance toward the small set of existing anti-Pseudomonal antibiotics. This seriously limits the ability to identify “hits” with antibiotic activity using whole-cell assays - as compounds that penetrate and can inhibit key metabolic pathways are often effluxed out before they measurably inhibit bacterial growth or viability. Approaches that identify novel small molecule inhibitors of key bacterial enzymes often fail when these small molecules cannot achieve effective intrabacterial concentrations - and our understanding of the chemistries that would allow for penetration and retention is woefully incomplete. In this application we use a diverse array of riboswitches, sensitive and specific RNA-based small molecule sensors, as rapid and quantitative indicators that bacterial physiology has been perturbed. By multiplexing several riboswitches that report on accumulation of the alarmones ZTP and ppGpp, as well as the toxic product of increased SAM utilization, SAH, we can effectively screen for “signatures” of a bacterial response to sub- MIC levels of small molecules. Our approach places these riboswitch reporters in isogenic MDR and efflux- deficient P. aeruginosa strains, simultaneously yielding information about both physical and structural chemical features that allow penetration and efflux-avoidance and identifying “hit” molecules that can be developed as leads for new antibacterial agents. Our medicinal chemistry approach will build on both types of knowledge, allowing novel anti-Pseudomonal compounds to be identified and optimized.


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: 2022 ( Subtotal = $1,047,570 )
2022	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	NEW HAVEN	USA	Allergy and Infectious Diseases Research	000	5	1/13/2022	NON-COMPETING CONTINUATION	$1,047,570
														Subtotal = $1,047,570

Issue Date FY: 2021 ( Subtotal = $1,090,845 )
2021	2021	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	NEW HAVEN	USA	Allergy and Infectious Diseases Research	000	4	2/5/2021	NON-COMPETING CONTINUATION	$1,090,845
														Subtotal = $1,090,845

Issue Date FY: 2020 ( Subtotal = $1,114,844 )
2020	2020	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	NEW HAVEN	USA	Allergy and Infectious Diseases Research	000	3	1/13/2020	NON-COMPETING CONTINUATION	$1,114,844
														Subtotal = $1,114,844

Issue Date FY: 2019 ( Subtotal = $1,135,599 )
2019	2019	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	NEW HAVEN	USA	Allergy and Infectious Diseases Research	000	2	1/29/2019	NON-COMPETING CONTINUATION	$1,135,599
														Subtotal = $1,135,599

Issue Date FY: 2018 ( Subtotal = $1,234,615 )
2018	2018	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	NEW HAVEN	USA	Allergy and Infectious Diseases Research	000	1	2/19/2018	NEW	$1,234,615
2018	2018	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	NEW HAVEN	USA	Allergy and Infectious Diseases Research	001	1	4/30/2018	NEW	$0
														Subtotal = $1,234,615

Grand Total All Awards = $5,623,473

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Exploiting Riboswitch Sensors to Reveal Antibiotics Uptake and Retention in Gram Negative Bacteria

Award Number: R01AI136794

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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