Research Project Leaders

Jeff North

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Aminoglycosides (AG) have broad antibiotic spectra against aerobic gram-positive and gram-negative bacteria as well as mycobacterial pathogens. AG toxicities include kidney tubular necrosis, vertigo, and, most notably, hearing loss. AG are used to treat multidrug-resistant tuberculosis (MDR-TB) and Mycobacterium abscessus complex (MABSC) infected patients (e.g. cystic fibrosis, bronchiectasis or chronic obstructive pulmonary disease). 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 cystic fibrosis patients infected with M. abscessus who received AG therapy experienced hearing loss. To date, there is no FDA-approved therapy available to prevent or treat hearing loss. A reduced reliance on AG therapy in mycobacterial infections will minimize hearing loss for patients infected with drug-resistant M. tb strains and nontuberculous 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. We propose to discover and develop anti-mycobacterial inhibitors with potent activity with improved pharmacokinetic profiles and no ototoxicity. Using ligand-based drug design and computer aided drug design. In vitro bioavailability and toxicity profiles will also be determined. 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 MmpL inhibitors. Our lab has developed novel MmpL3 (Mycobacterium membrane protein Large 3) inhibitors showing excellent promise for the treatment of mycobacterial infections, including Mycobacterium tuberculosis, the causative pathogen for tuberculosis. The design and synthesis of a novel series of MmpL3 inhibitors led us to identify a number of analogs with 0.06-8 µg/mL potency against various slow- and fast-growing mycobacterial pathogens of clinical interest. Consistent with earlier findings in M. tuberculosis, our preliminary evidence indicates that ICs (Indole-2-carboxamide) kill Mycobacterium abscessus isolates through the inhibition of the essential mycolic acid transporter, MmpL3. Mycolic acids, which are long α-alkylated β-hydroxylated fatty acids, are primary constituents of the mycobacterial outer membrane (also referred to as mycomembrane) and inhibition of translocation across the plasma membrane through the inhibition of MmpL3 has a rapid bactericidal effect on the cells. We believe MmpL3 inhibitors are an important discovery of a new chemotype that can be used for the treatment of mycobacterial infections.

Litao Tao

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Transcription factor POU4F3 is indispensable for the differentiation and homeostasis of sensory hair cells, the essential cell type converting mechanical vibrations into electrical signals for hearing function. During hair cell differentiation, the pioneer factor activity of POU4F3 is required for ATOH1 to access many inaccessible elements to up-regulate hair cell genes. In mature hair cells, reduction of POU4F3 transcription activity due to mutations in one allele leads to hair cell death and hence progressive hearing loss (DFNA15,autosomal dominant non-syndromic hearing loss 15). It remains unclear how the expression of POU4F3 gene is regulated at different developmental stages and there is no feasible method to stimulate the POU4F3 gene in a cell type-specific and temporal-regulated manner. Using mouse models, we plan to investigate the regulatory roles of Pou4f3 enhancers to understand the transcription regulation of the Pou4f3 gene. In addition, we will epigenetically manipulate Pou4f3 enhancers to stimulate Pou4f3 expression specifically in hair cells for a potential therapeutic treatment of hearing loss in DFNA15 patients. Through this proposed study, we will gain a better understanding of how POU4F3 gene is regulated at the transcription level, and potentially find a therapeutic approach to treat DFNA15 patients.

Justine Renauld

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Ménière’s disease (MD) is characterized by symptoms such as hearing loss and vertigo, but its underlying cause is still unclear. Research on the temporal bones of MD patients has identified a condition known as endolymphatic hydrops, marked by an expansion of the scala media, indicating a disruption in fluid balance within the inner ear. Endolymph, a vital fluid within the membranous labyrinth, is essential for maintaining hearing and balance. However, the mechanisms that regulate this fluid are not yet fully understood. Given the critical role of fluid homeostasis in the inner ear, our research aims to investigate the formation of endolymphatic hydrops and its impact on neuronal dysfunction.

In this research, we will investigate inner ear dysfunction in an animal model of endolymphatic hydrops. We will correlate hearing and balance thresholds with the ionic and protein composition of endolymph and perilymph. We will test if there is degradation of the blood endolymph barrier during development of endolymphatic hydrops. Finally, we will conduct transcriptomic analysis on the hydropic neurons to better understand the cause of neuronal dysfunction during the development of endolymphatic hydrops. 

These studies are essential for comprehending potential mechanisms underlying disruptions in inner ear homeostasis and the development of conditions like MD. This understanding will be essential in developing targeted therapies for MD and related conditions.