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ACS Infect Dis. 2019 Jul 25. doi: 10.1021/acsinfecdis.9b00172. [Epub ahead of print]

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

Author information

1
Aix-Marseille Université , CNRS, LISM, Institut de Microbiologie de la Méditerranée , Marseille , France 13402 Cedex 20.
2
Department of Chemistry and Biochemistry , University of Missouri-St. Louis , One University Boulevard , St. Louis , Missouri 63121 , United States.
3
APHP, GHU PIFO , Hôpital Raymond-Poincaré-Hôpital Ambroise-Paré , 92100 Boulogne-Billancourt , France.
4
2I, UVSQ, INSERM UMR 1173 , Université Paris-Saclay , 78035 Versailles , France.
5
Aix Marseille Université , CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Marseille Protéomique , 13273 Marseille Cedex 09, France.
6
Institut de Recherche en Infectiologie de Montpellier (IRIM), CNRS, UMR 9004 , Université de Montpellier , 34293 Montpellier , France.
7
IRIM, INSERM , 34293 Montpellier , France.

Abstract

Twelve new Cyclophostin and Cyclipostins analogues (CyC19-30) 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 (CyC17/CyC18β/CyC25/CyC26) or intramacrophage residing mycobacteria (CyC7(α,β)/CyC8(α,β)) 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 CyC17/CyC26, 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.

KEYWORDS:

activity based-protein profiling; drug susceptibility; proteomics analysis; total synthesis

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