Cyclipostins and Cyclophostin Analogues as Multitarget Inhibitors That Impair Growth of .

Résumé

Twelve new Cyclophostin and Cyclipostins analogues () were synthesized, thus extending our series to 38 . Their antibacterial activities were evaluated against four pathogenic mycobacteria (, , BCG, and ) and two Gram negative bacteria. The displayed very low toxicity toward host cells and were only active against mycobacteria. Importantly, several were active against extracellular (///) or intramacrophage residing mycobacteria (/) with minimal inhibitory concentrations (MIC) 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 /, mostly being involved in lipid metabolism and/or in cell wall biosynthesis. Overall, these results strengthen the selective activity of the against mycobacteria, including the most drug-resistant , through the cumulative inhibition of a large number of Ser- and Cys-enzymes participating in key physiological processes.