TY - JOUR
T1 - Cyclipostins and Cyclophostin Analogues as Multitarget Inhibitors That Impair Growth of Mycobacterium abscessus
AU - Madani, Abdeldjalil
AU - Ridenour, Jeremy N.
AU - Martin, Benjamin P.
AU - Paudel, Rishi R.
AU - Basir, Anosha Abdul
AU - Moigne, Vincent Le
AU - Herrmann, Jean-Louis
AU - Audebert, Stephane
AU - Camoin, Luc
AU - Kremer, Laurent
AU - Spilling, Christopher
AU - Canaan, Stephane
AU - Cavalier, Jean-Francois
N1 - 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.
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
KW - bacteria
KW - infectious diseases
KW - inhibitors
KW - innumology
KW - peptides and protines
UR - https://pubs.acs.org/doi/10.1021/acsinfecdis.9b00172
U2 - 10.1021/acsinfecdis.9b00172
DO - 10.1021/acsinfecdis.9b00172
M3 - Article
VL - 5
JO - ACS Infectious Diseases
JF - ACS Infectious Diseases
ER -