Résumé
Non-tuberculous mycobacteria (NTM) infections are increasingly being reported worldwide. Intrinsic antibiotic resistance, impermeability of the cell wall to inhibitors, cleavage, modification of drugs within the pathogens and efficient efflux pumps are major obstacles to the treatment of NTM illness. The cure rate of NTM treatment is low, lengthy and costly, which in part is the result of low potency, poor clinical response, severe side-effects. To overcome these problems, new inhibitor targets, compounds and novel combinatory approaches are needed. As a strictly aerobic class of pathogens, NTM depend on the oxidative phosphorylation pathway to form ATP by F1 FO-ATP synthase. Recent studies demonstrated that the NTM F1FO -ATP synthase is a potent target to inhibit growth of NTM by either binding to the F1- [1-3] or FO domain of this engine [4-5]. Here we present new and highly potent inhibitors with high efficacy against a broad spectrum of fast- and slow-growing NTMs including clinical isolates. They are mycobacterial-specific and non-toxic to the human gut biofilm or eukaryotic cells and enhance the potency of a variety of existing NTM drugs, thereby overcome the issues of drug tolerance and resistance. Finally, their chemical synthesis makes these molecules cost-effective and attractive inhibitors for pharma and healthcare.[1] P. Ragunathan, T. Dick, G. Grüber, Anti-Mycobacterium abscessus activity of tuberculosis F-ATP synthase inhibitor GaMF1. Antimicrob. Agents and Chemother, 66 (2022) e0001822.[2] S. Joon, A. Harikishore, C.-F. Wong, P. Ragunathan, T. Dick, G. Grüber, Atomic solution structure of Mycobacterium abscessus F-ATP synthase subunit ε and identification of Ep1MabF1 as a targeted inhibitor, FEBS J, 289 (2022) 6308-6323.[3] C.-F. Wong, W.-G. Saw, S. Basak, M. Sano, H. Ueno, H. W. Kerk, D. Litty, P. Ragunathan, T. Dick, V. Müller, H. Noji, G. Grüber, Structural elements involved in ATP hydrolysis inhibition and ATP synthesis of tuberculosis and non-tuberculous mycobacterial F-ATP synthase decipher new targets for inhibitors. Antimicrobe. Agents and Chemother, 66 (2022) (12):e0105622.[4] J.P. Sarathy, U.S. Ganapathy, M.D. Zimmerman, V. Dartois, M. Gengenbacher, T. Dick, TBAJ-876, a 3,5-Dialkoxypyridine Analogue of Bedaquiline, Is Active against Mycobacterium abscessus, Antimicrob Agents Chemother, 64 (2020) e02404-19.[5] P. Ragunathan, P. Sae-Lao, C. Hamela, M. Alcaraz, A. Krah, W.H. Poh, C.J.E. Pee, A.Y.H. Lim, S.A. Rice, P. Pethe, P.J. Bond, T. Dick, L. Kremer, R.W. Bates, G. Grüber, High efficacy of the F-ATP synthase inhibitor TBAJ-5307 against non-tuberculous mycobacteria in vitro and in vivo, J Biol Chem, 300 (2024) 105618.