Development of tetracycline analogues with increased aqueous stability for the treatment of mycobacterial infections

Tetracycline analogs from the minocycline family have recently shown promise for the treatment of non-tuberculous mycobacterial infections. However, current tetracycline and minocycline therapeutics can be limited by tolerability, stability, or inactivation by TetX. In this study, a series of novel 9-heteroaryl substituted minocycline analogs were designed and synthesized, which resulted in analogs with good in vitro activity against Mycobacterium tuberculosis and Mycobacterium abscessus, stability in water for more than 7 days, avoidance of TetX inactivation in M. abscessus, and a lack of cytotoxicity in HepG2 mammalian cells. In vivo efficacy was confirmed for the tetracycline analogs in an acute model of GM-CSF KO mice infected with M. abscessus, displaying superior efficacy to standard-of-care antibiotic clarithromycin. Molecular modeling and potentiation assays demonstrate avoidance of MabTetX, and the structure-activity relationships of the series are discussed herein for M. tuberculosis and M. abscessus.