# Development of Novel Therapeutics for Treatment of Mycobacterial Infections

> **NIH NIH P20** · CREIGHTON UNIVERSITY · 2021 · $254,995

## Abstract

Aminoglycosides (AG) have broad antibiotic spectra against aerobic gram-positive and gram-negative bacteria 
and mycobacterial pathogens. AG toxicities include kidney tubular necrosis, vertigo, and, most notably, hearing 
loss. Regarding the use of AG in mycobacterial infections, they are used to treat multidrug-resistant 
tuberculosis (MDR-TB) and Mycobacterium abscessus complex (MABSC) infected patients with cystic fibrosis 
(or other structural lung disorders). Studies have shown that 55-58% of patients infected with MDR-TB who 
received amikacin as part of their therapy, experienced hearing loss due to its ototoxic effects. Likewise, up to 
27% of patients with cystic fibrosis infected with M. abscessus who received aminoglycoside therapy 
experienced hearing loss. To date, there is no FDA-approved method or therapy available to prevent or 
treat hearing loss. Reduced reliance on aminoglycoside use in mycobacterial infections should minimize 
hearing loss risk for patients infected with drug-resistant Mycobacterium tuberculosis (M. tb) strains and 
nontuberculous (NTM) mycobacteria. 
We have discovered a novel series of small molecules (indole-2-carboxamides and acetamides) that have potent 
activity against a panel of mycobacteria. Two of our lead candidates had poor oral absorption yet achieved 
efficacy in a mouse model of M. abscessus infection. Therefore, we propose to discover and develop antimycobacterial 
inhibitors with potent activity with improved pharmacokinetic profiles and no ototoxicity. This will 
be accomplished using ligand-based drug design and computer aided drug design. In vitro bioavailability and 
toxicity profiles will also be determined for the inhibitors. Finally, potent anti-NTM agents with optimized 
bioavailability and toxicity profiles will be subjected to macromolecular mechanism of action studies, ensuring 
future compounds remain on target as Mycobacterial membrane protein Large 3 (MmpL3) inhibitors.

## Key facts

- **NIH application ID:** 10449140
- **Project number:** 1P20GM139762-01
- **Recipient organization:** CREIGHTON UNIVERSITY
- **Principal Investigator:** Elton Jeffrey North
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $254,995
- **Award type:** 1
- **Project period:** 2021-07-12 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10449140

## Citation

> US National Institutes of Health, RePORTER application 10449140, Development of Novel Therapeutics for Treatment of Mycobacterial Infections (1P20GM139762-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10449140. Licensed CC0.

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