Thursday, November 21, 2024 11/21/2024

Simultaneous Treatment of Viral and Bacterial Otitis Media Using Plant Natural Products

Award Number: R21DC019206
ORGANIZATION: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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1 Project Summary 2 Otitis media (OM) is a major child health burden. It is the most commonly diagnosed pediatric disease and the 3 #1 reason for antimicrobial prescription to US children. Moreover, 62% of children with OM demonstrate viral 4 infections in their middle ear, to which antibiotics are ineffective but prescribed nonetheless. The widespread use 5 of systemic antibiotics against a disease of such high prevalence and recurrence is believed to breed antibiotic 6 resistance. To treat viral and bacterial infections simultaneously, we will design and synthesize sophisticated 7 plant natural products (PNPs) and their derivatives with no known drug resistance,. The state-of-the-art synthetic 8 biology pipeline that we pioneered will enable the optimization and scalable production of antimicrobial PNPs 9 with enhanced permeability and antimicrobial efficacy. The novel PNP compounds will be delivered locally into 10 the middle ear using a proven hydrogel, which is an easy-to-apply liquid at room temperature and gels quickly 11 and firmly upon contacting warm tympanic membrane (TM). Chemical permeation enhancers inside the gel can 12 overcome the impermeable barrier of the TM and bring the PNPs into the middle ear. We have demonstrated 13 that a single application of the hydrogel formulation provides enough antibiotics for a 7-day treatment, eradicating 14 the infection in a chinchilla OM model. 15 The current application attempts to completely eliminate antibiotic usage in this prevalent childhood disease and 16 to mitigate OM-related drug resistance by using a stand-alone therapy that treats both bacterial and viral 17 infections. It focuses on the production and modification of berberine, an alkaloid derived from medicinal plants. 18 Berberine has demonstrated antimicrobial effects against Gram-positive and -negative bacteria including MRSA 19 and has shown antiviral properties against multiple viruses. This work will leverage our experience in PNP 20 biosynthesis to reconstruct a biosynthetic pathway in yeast for berberine production. We will incorporate diverse 21 tailoring enzymes (e.g., halogenases) and modified precursor molecules to produce modified berberine 22 derivatives that are difficult to achieve by conventional chemical synthesis. The therapeutic efficacy and 23 biocompatibility of the modified berberine derivatives will be tested using an established chinchilla OM model. 24 The knowledge and techniques developed in this project will provide new insight into overcoming the biological 25 barriers in the ear via molecular design and new treatments for acute and recurrent OM. The focus on berberine 26 is based on its known antimicrobial effect, and the general methodologies are applicable to other PNPs that 27 could treat ear diseases beyond OM.


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	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Research Related to Deafness and Communication Disorders	000	3	10/11/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $146,636 )
2023	2023	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Research Related to Deafness and Communication Disorders	001	3	1/13/2023	NON-COMPETING CONTINUATION	$14,664
2023	2023	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Research Related to Deafness and Communication Disorders	000	3	11/18/2022	NON-COMPETING CONTINUATION	$131,972
														Subtotal = $146,636

Issue Date FY: 2022 ( Subtotal = $146,952 )
2022	2022	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Research Related to Deafness and Communication Disorders	000	2	11/19/2021	NON-COMPETING CONTINUATION	$132,256
2022	2022	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Research Related to Deafness and Communication Disorders	001	2	4/20/2022	NON-COMPETING CONTINUATION	$14,696
														Subtotal = $146,952

Issue Date FY: 2021 ( Subtotal = $147,240 )
2021	2021	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Research Related to Deafness and Communication Disorders	000	1	12/1/2020	NEW	$147,240
														Subtotal = $147,240

Grand Total All Awards = $440,828

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Simultaneous Treatment of Viral and Bacterial Otitis Media Using Plant Natural Products

Award Number: R21DC019206

ORGANIZATION: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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