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Ototoxicity of modified aminoglycosides

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R44AI172739-01
Agency Tracking Number: R44AI172739
Amount: $1,989,206.00
Phase: Phase II
Program: SBIR
Solicitation Topic Code: NIAID
Solicitation Number: PA21-259
Timeline
Solicitation Year: 2021
Award Year: 2022
Award Start Date (Proposal Award Date): 2022-07-11
Award End Date (Contract End Date): 2025-06-30
Small Business Information
900 B West Faris Road
Greenville, SC 29605
United States
DUNS: 831389122
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: Yes
Principal Investigator
 SANDRA STORY
 (864) 655-7244
 sandra.story@nubadllc.com
Business Contact
 DEV ARYA
Phone: (864) 448-4428
Email: 101arya@gmail.com
Research Institution
N/A
Abstract

PROJECT SUMMARY
Aminoglycosides 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. Although new generations of antibiotics have emerged in the
last decades, aminoglycoside antibiotics maintain a leading role in treatment of acute infections and for specific
indications such as tuberculosis or the containment of pseudomonas bacteria in patients with cystic fibrosis.
Owing to their broad antibacterial spectrum and efficacy against resistant bacterial diseases, aminoglycoside
antibiotics continue to be indispensable. However, their use has been limited due to side effects. The major side
effects accompanying aminoglycoside treatment are nephrotoxicity and ototoxicity, including cochlear damage
and vestibular disorders. Nephrotoxicity affects about 20% of patients and is usually reversible, while ototoxicity
is irreversible. It is estimated that cochlear damage occurs in 20% and vestibular disorders in 15% of those
receiving aminoglycoside antibiotics, but the incidence increases markedly to 80% in long-term treatment for
tuberculosis. The pathological feature of aminoglycoside-induced ototoxicity is loss of mechanosensory hair
cells in the inner ear. Hair cell loss begins at the base of the cochlea and proceeds toward the apex. Hair cells
are specialized mechanoreceptors that convert auditory and vestibular mechanical stimuli into electrical signals.
These cells are responsible for the detection of sound and equilibrium. Since mammalian hair cells lack the
ability to regenerate, the loss of or damage to hair cells is the leading cause of permanent hearing impairments
and vestibular disorders. Although a series of biological events and cell death pathways are known to be involved
in aminoglycoside-induced hair cell death, no established clinical therapies for prevention or amelioration of this
disability are available. Aminoglycoside-induced ototoxicity reduces the quality of life of millions of affected
individuals and confers a great economic cost. Therefore, development of new efficacious synthetic
aminoglycoside derivatives, but without the problematic side effects, will provide a fundamental approach to
prevent ototoxicity. Since the ototoxicity potential and organ preference varies among the different
aminoglycoside antibiotics, small changes in structure may greatly influence toxicity, providing great possibility
to find new aminoglycoside derivatives. We are developing fast and low-cost methods to develop
aminoglycosides with broad spectrum anti-infective activities, but with reduced ototoxicity. In this project, we will
identify novel aminoglycoside based anti-infectives, that show reduced ototoxicity. This work addresses an
important health issue, anti-infective drug ototoxicity, and presents creative steps towards a novel solution to this
problem.
Unless innovative strategies are developed to produce robust and effective new classes of non-toxic antibiotics,
health care costs will continue to climb and we will completely lose our ability to combat even the most common
infection. One of the challenges of research in drug development is to find ways to use the increasing knowledge
of the mechanisms underlying disease biology, and toxicities, along with disease transformation and progression
to develop novel therapeutic strategies for MDR, XDR, and PDR infections. One of the biggest bottlenecks in
the advancement of drugs to the clinic and eventual limitation in the clinical usage, is the toxicity of the drug.
This problem becomes even more acute when the drugs have to be used for extended periods of time (months),
such as for fungal infections in immunocompromised patients. We have therefore focused our efforts in
identifying the toxicity pathways for individual drug classes, such as aminoglycosides, and addressed these
issues at the very outset. Since aminoglycoside-induced hair cell loss in explants is similar to that in humans,
we will first use mouse organ culture for a secondary screening of the top compounds without toxicity. We will
then use pigmented guinea pigs to evaluate auditory function by measurement of auditory brainstem responses,
count loss of sensory hair cell loss, and assess renal function with serum for the top compounds. The results of
this project will help us identify novel aminoglycosides with high efficacy against microbes of interest, but with
reduced toxicity.
The work proposed here, a multidisciplinary effort using rapid methods of synthesis, inhibition, and ototoxicity
assays, will be further developed in this Phase II application using in vivo efficacy and ototoxicity studies using
guinea pig models. We propose using novel aminoglycoside modifications, patented NUBAD assays, mouse
organ culture studies, guinea pigs, to identify conjugates that show reduced ototoxicities, opening possibilities
for developing drugs that can target resistant pathogens, but with much improved therapeutic indices.

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

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