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

Abstract

Twelve new Cyclophostin and Cyclipostins analogues (<b>CyC</b>_{<b>19</b>-<b>30</b>}) were synthesized, thus extending our series to 38 <b>CyCs</b>. Their antibacterial activities were evaluated against four pathogenic mycobacteria (<i>Mycobacterium abscessus</i>, <i>Mycobacterium marinum</i>, <i>Mycobacterium bovis</i> BCG, and <i>Mycobacterium tuberculosis</i>) and two Gram negative bacteria. The <b>CyCs</b> displayed very low toxicity toward host cells and were only active against mycobacteria. Importantly, several <b>CyCs</b> were active against extracellular <i>M. abscessus</i> (<b>CyC</b>_<b>17</b>/<b>CyC</b>_<b>18β</b>/<b>CyC</b>_<b>25</b>/<b>CyC</b>_<b>26</b>) or intramacrophage residing mycobacteria (<b>CyC</b>_{<b>7(α,β)</b>}/<b>CyC</b>_{<b>8(α,β)</b>}) with minimal inhibitory concentrations (MIC₅₀) 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 <b>CyC</b>_<b>17</b>/<b>CyC</b>_<b>26</b>, mostly being involved in lipid metabolism and/or in cell wall biosynthesis. Overall, these results strengthen the selective activity of the <b>CyCs</b> against mycobacteria, including the most drug-resistant <i>M. abscessus</i>, through the cumulative inhibition of a large number of Ser- and Cys-enzymes participating in key physiological processes.