MmPPOX Inhibits Mycobacterium tuberculosis Lipolytic Enzymes Belonging to the Hormone-Sensitive Lipase Family and Alters Mycobacterial Growth

• DOI: 10.1371/journal.pone.0046493
• Publication Date: 2012-09-30T22:57:57Z
• Authors: Vincent Delorme; Sadia V. Diomandé; Luc Dedieu; Jean-François Cav...; Frédéric Carrière; Laurent Kremer; Julien Leclaire; Frédéric Fotiadu; Stéphane Canaan
• Keywords: 0301 basic medicine; fusarium solani; 572; [SPI.GPROC] Engineering Sciences [physics]/Chemical and Process Engineering; [SDV]Life Sciences [q-bio]; Science; Lactones; 03 medical and health sciences; Bacterial Proteins; [SDV.IDA]Life Sciences [q-bio]/Food engineering; [SPI.GPROC]Engineering Sciences [physics]/Chemical and Process Engineering; Enzyme Inhibitors; enzyme lipolytique; cutinase; mycobacterium tuberculosis; Orlistat; Oxadiazoles; 0303 health sciences; séquence génomique; Q; R; Mycobacterium tuberculosis; [SDV.IDA] Life Sciences [q-bio]/Food engineering; Sterol Esterase; Recombinant Proteins; Anti-Bacterial Agents; 3. Good health; [SDV] Life Sciences [q-bio]; Molecular Weight; Kinetics; Medicine; triacylglycerol; Research Article

Lipid metabolism plays an important role during the lifetime of Mycobacterium tuberculosis, the causative agent of tuberculosis. Although M. tuberculosis possesses numerous lipolytic enzymes, very few have been characterized yet at a biochemical/pharmacological level. This study was devoted to the M. tuberculosis lipolytic enzymes belonging to the Hormone-Sensitive Lipase (HSL) family, which encompasses twelve serine hydrolases closely related to the human HSL. Among them, nine were expressed, purified and biochemically characterized using a broad range of substrates. In vitro enzymatic inhibition studies using the recombinant HSL proteins, combined with mass spectrometry analyses, revealed the potent inhibitory activity of an oxadiazolone compound, named MmPPOX. In addition, we provide evidence that MmPPOX alters mycobacterial growth. Overall, these findings suggest that the M. tuberculosis HSL family displays important metabolic functions, thus opening the way to further investigations linking the involvement of these enzymes in mycobacterial growth.