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Aminoglycosides with reduced ototoxicity via miRNA targeting

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R41AI142856-01A1
Agency Tracking Number: R41AI142856
Amount: $754,902.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: NIAID
Solicitation Number: PA18-575
Timeline
Solicitation Year: 2018
Award Year: 2019
Award Start Date (Proposal Award Date): 2019-03-15
Award End Date (Contract End Date): 2021-02-28
Small Business Information
900 B W FARIS RD
Greenville, SC 29605-4255
United States
DUNS: 831389122
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: Yes
Principal Investigator
 DEV ARYA
 (864) 656-1106
 dparya@clemson.edu
Business Contact
 DEV ARYA
Phone: (864) 656-1106
Email: 101arya@gmail.com
Research Institution
 CLEMSON UNIVERSITY
 
230 KAPPA STREET, STE. 200
CLEMSON, SC 29634-0001
United States

 Nonprofit college or university
Abstract

PROJECT SUMMARYAminoglycosides are one of the cheapest and well-known antibiotics in
clinical use for over 70 years, but one of the major limitations in their use is their
ototoxicity. We are developing fast and low cost methods to develop
aminoglycosides with anti- ribosomal activities and reduced toxicity. In this project,
we will identify novel aminoglycoside antibacterials, that show reduced ototoxicity.
Complexes between ribosomal components will be exploited as targets for small
molecule drug libraries that- inactivate the ribosome, stopping bacterial protein
synthesis and causing bacterial death while reducing toxicity. This work addresses
an important health issue, antibiotic ototoxicity, and presents creative steps towards
a novel solution to this problem.The work proposed here, a multidisciplinary effort using a miRNA binding and
inhibition approach, coupled with antibacterial screening and ototoxicity studies using
guinea pig models, describes the development and validation of a rapid way to
generate novel aminosugar rRNA binders as non-toxic antibacterial therapeutics. The
success of the proposed work would be a significant addition to currently available
approaches in antibacterial therapy. We propose using novel aminoglycoside
modifications and patented NUBAD assays to identify conjugates that show reduced
toxicities, opening possibilities for developing RNA targeted therapeutics with reduced
toxicity.PROJECT NARRATIVE
The proposed project presents a strategy for developing novel aminoglycoside
therapeutics with novel miRNA and rRNA discriminating recognition motifs to reduce
drug ototoxicities. Antimicrobial resistance occurs when microorganisms (often
infectious bacteria, viruses, and certain parasites) are no longer sensitive to drugs
that were previously used to treat them; this is of global concern because it
hampers our ability to control infectious disease and increases the costs of health
care. In order to combat this world-wide problem, innovative strategies for antibiotic
drug design must be implemented. The proposed research describes a strategy for
improving the therapeutic index of aminoglycosides by designing novel structures
that lower their ototoxicity and evade common resistance pathways.

* Information listed above is at the time of submission. *

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