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High Throughput Screening to Discover Novel Toxin Inhibitors Relevant to the Treatment of Otitis Media

Award Number: U01DC014756
ORGANIZATION: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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¿ DESCRIPTION (provided by applicant): Otitis media (OM) is the second most common disease of childhood, and an important OM pathogen that can cause both acute and recurrent disease is nontypeable Haemophilus influenzae (NTHi). We have identified a toxin-antitoxin protein pair in NTHi, VapBC-1, as being crucial for the ability of the organism to survive during experimental OM. Upon encountering stressful conditions, the VapB-1 antitoxin is degraded and the VapC-1 ribonuclease toxin is freed to cleave mRNA, arresting bacterial growth. This state of dormancy facilitates nonspecific antibiotic tolerance, as most antimicrobials are designed to inhibit essential cellular functions necessary for replication. Further, it allows a subpopulation f the infecting bacteria to survive treatment and resume growth, resulting in recurrent disease. Homologues of this protein pair are very highly conserved in numerous bacterial genomes. We intend to target this protease-mediated molecular switch and block the ability of the organism to go into stasis using a high-throughput screening approach to discover and validate novel chemical probes that interfere with VapC-1 toxin activity. These small molecule probes will inhibit the ability of the organism to enter into a bacteriostatic state, allowing antimicrobial therapy to kill the bacteria that were previously tolerant due to dormancy. We propose the following Specific Aims: 1) Use our innovative miniaturized and validated fluorescence-quenching ribonuclease interference assay to screen the NCATS library of small molecules for toxin-targeted compounds (TTCs); 2) perform secondary screens against the hits including a different detection wavelength, a specificity assay and a cytotoxicity assay; 3) validate the specificity of the non-cytotoxic TTCs in vitro using an engineered bacterial strain with inducible VapC-1 toxin expression, and 4) determine the effectiveness of the TTCs to treat NTHi infections of primary human respiratory tissues held at the air-liquid interface. Treatment with the chemical probes validated in this study could be used in conjunction with antibiotics to achieve a complete eradication of infecting organisms, giving clinicians a novel adjunctive therapy for their patients with recurrent 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: 2020 ( Subtotal = -$65,574 )
2020	2017	OLD DOMINION UNIVERSITY	5115 HAMPTON BLVD	NORFOLK	VA	23529	NORFOLK CITY	USA	Research Related to Deafness and Communication Disorders	000	3	12/19/2019	NON-COMPETING CONTINUATION	-$65,574
														Subtotal = -$65,574

Issue Date FY: 2019 ( Subtotal = $0 )
2019	2017	OLD DOMINION UNIVERSITY	5115 HAMPTON BLVD	NORFOLK	VA	23529	NORFOLK CITY	USA	Research Related to Deafness and Communication Disorders	000	3	2/13/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $0 )
2018	2017	OLD DOMINION UNIVERSITY	5115 HAMPTON BLVD	NORFOLK	VA	23529	NORFOLK CITY	USA	Research Related to Deafness and Communication Disorders	000	3	6/5/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2017 ( Subtotal = $417,447 )
2017	2017	OLD DOMINION UNIVERSITY	5115 HAMPTON BLVD	NORFOLK	VA	23529	NORFOLK CITY	USA	Research Related to Deafness and Communication Disorders	001	3	6/29/2017	NON-COMPETING CONTINUATION	$406,393
2017	2017	OLD DOMINION UNIVERSITY	5115 HAMPTON BLVD	NORFOLK	VA	23529	NORFOLK CITY	USA	Research Related to Deafness and Communication Disorders	000	2	6/8/2017	SUPPLEMENT FOR EXPANSION	$11,054
														Subtotal = $417,447

Issue Date FY: 2016 ( Subtotal = $340,340 )
2016	2016	OLD DOMINION UNIVERSITY RESEARCH FOUNDATION	P.O. BOX 6369	NORFOLK	VA	23508	NORFOLK CITY	USA	Research Related to Deafness and Communication Disorders	000	2	7/5/2016	NON-COMPETING CONTINUATION	$340,340
														Subtotal = $340,340

Issue Date FY: 2015 ( Subtotal = $262,157 )
2015	2015	OLD DOMINION UNIVERSITY RESEARCH FOUNDATION	P.O. BOX 6369	NORFOLK	VA	23508	NORFOLK CITY	USA	Research Related to Deafness and Communication Disorders	000	1	8/13/2015	NEW	$262,157
														Subtotal = $262,157

Grand Total All Awards = $954,370

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High Throughput Screening to Discover Novel Toxin Inhibitors Relevant to the Treatment of Otitis Media

Award Number: U01DC014756

ORGANIZATION: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

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