Cyclipostins and Cyclophostin Analogues as Multitarget Inhibitors That Impair Growth of <i>Mycobacterium abscessus</i>

Twelve new Cyclophostin and Cyclipostins analogues ( CyC 19 - 30 ) were synthesized, thus extending our series to 38 CyCs . Their antibacterial activities were evaluated against four pathogenic mycobacteria ( Mycobacterium abscessus , Mycobacterium marinum , Mycobacterium bovis BCG, and Mycobacterium tuberculosis ) and two Gram negative bacteria. The CyCs displayed very low toxicity toward host cells and were only active against mycobacteria. Importantly, several CyCs were active against extracellular M. abscessus ( CyC 17 / CyC 18β / CyC 25 / CyC 26 ) or intramacrophage residing mycobacteria ( CyC 7(α,β) / CyC 8(α,β) ) with minimal inhibitory concentrations (MIC 50 ) values comparable to or better than those of amikacin or imipenem, respectively. An activity-based protein profiling combined with mass spectrometry allowed identification of the potential target enzymes of CyC 17 / CyC 26 , mostly being involved in lipid metabolism and/or in cell wall biosynthesis. Overall, these results strengthen the selective activity of the CyCs against mycobacteria, including the most drug-resistant M. abscessus , through the cumulative inhibition of a large number of Ser- and Cys-enzymes participating in key physiological processes.