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Development of Nanoparticle Antibiotic Adjuvant for the Treatment of Chronic Suppurative Otitis Media

Award Number: R21AI154097
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary / Abstract We request NIH support to investigate the use of functionalized gold nanoclusters as an adjuvant therapy for chronic suppurative otitis media (CSOM). CSOM is characterized by a chronically discharging infected middle ear that is most frequently caused by Pseudomonas aeruginosa (PA) and is a leading cause of permanent hearing loss. In CSOM, PA exists in bacterial communities known as biofilms. Fluoroquinolone eardrops are the primary method of treatment due to its non-ototoxicity. However, this treatment is ineffective in fully eradicating the infection. This is a result of the inability of fluoroquinolone to target a subpopulation of metabolically inactive bacteria known as persister cells within the biofilms. Persister cells repopulate the biofilm niche after therapy is discontinued, causing a relapse of CSOM. The end result is multiple rounds of surgery and a lifelong struggle with this disease. There is a large unmet medical need to develop new medical therapies aimed at persister cells in biofilms of CSOM. Our lab has recently created and validated a novel PA CSOM animal model with bioluminescent strains of PA allowing real time tracking of disease. It mimics the human condition by persisting beyond six months, is recalcitrant to topical fluoroquinolone therapy, and leads to hair cell death (i.e. hearing loss) over time. Using our unique model of PA CSOM, we are now able to test novel therapeutics for CSOM. Consequently, we have created an anionic hydrophilically functionalized gold nanocluster covalently conjugated with cell penetrating peptide (AuNC@CPP) as an adjuvant for fluoroquinolones. We have shown, in vitro, that co-administration of the AuNC@CPP with ofloxacin completely eliminates persister cells in both stationary phase and biofilms of PA. The exceptional killing ability of AuNC@CPP plus ofloxacin opens up the possibility to develop the first therapeutic that specifically targets PA CSOM. We theorize that our AuNC@CPP combined with ofloxacin therapy can eradicate PA CSOM in vivo. Because our preliminary data shows that AuNC@CPP does not increase intracellular ofloxacin concentration, we hypothesize that AuNC@CPP acts as both an enhancer of reactive oxygen species (ROS)-mediated ofloxacin lethality and inhibits bacterial DNA repair. We propose to determine the mechanism(s) behind how AuNC@CPP potentiates ofloxacin lethality of persister cells by measuring intracellular ROS production and evaluating RecA inhibition followed by in vivo studies for efficacy and ototoxicity in comparison to ofloxacin alone. The proposed work will develop the first adjuvant therapy that specifically targets recalcitrant CSOM and lays the foundation for future research of this treatment in other chronic biofilm infections.


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: 2023 ( Subtotal = $0 )
2023	2021	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Allergy and Infectious Diseases Research	000	2	8/25/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $198,180 )
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Allergy and Infectious Diseases Research	000	2	6/2/2021	NON-COMPETING CONTINUATION	$198,180
														Subtotal = $198,180

Issue Date FY: 2020 ( Subtotal = $237,575 )
2020	2020	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Allergy and Infectious Diseases Research	000	1	6/26/2020	NEW	$237,575
														Subtotal = $237,575

Grand Total All Awards = $435,755

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Development of Nanoparticle Antibiotic Adjuvant for the Treatment of Chronic Suppurative Otitis Media

Award Number: R21AI154097

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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