Development of Novel Therapeutics for Treatment of Mycobacterial Infections

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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.