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- 저자 : Pophillat, Matthieu (검색결과 1 건)
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Oxadiazolone derivatives, new promising multi-target inhibitors against <i>M. tuberculosis</i>
Nguyen, Phuong Chi,Delorme, Vincent,Bé,narouche, Anaï,s,Guy, Alexandre,Landry, Valé,rie,Audebert, Sté,phane,Pophillat, Matthieu,Camoin, Luc,Crauste, Cé,line,Galano, Jean-Ma Elsevier 2018 Bioorganic chemistry Vol.81 No.-
<P><B>Abstract</B></P> <P>A set of 19 oxadiazolone (<B>OX</B>) derivatives have been investigated for their antimycobacterial activity against two pathogenic slow-growing mycobacteria, <I>Mycobacterium marinum</I> and <I>Mycobacterium bovis</I> BCG, and the avirulent <I>Mycobacterium tuberculosis</I> (<I>M. tb</I>) mc<SUP>2</SUP>6230. The encouraging minimal inhibitory concentrations (MIC) values obtained prompted us to test them against virulent <I>M. tb</I> H37Rv growth either in broth medium or inside macrophages. The <B>OX</B> compounds displayed a diversity of action and were found to act either on extracellular <I>M. tb</I> growth only with moderated MIC<SUB>50</SUB>, or both intracellularly on infected macrophages as well as extracellularly on bacterial growth. Of interest, all <B>OX</B> derivatives exhibited very low toxicity towards host macrophages. Among the six potential <B>OXs</B> identified, <B>HPOX</B>, a selective inhibitor of extracellular <I>M. tb</I> growth, was selected and further used in a competitive labelling/enrichment assay against the activity-based probe Desthiobiotin-FP, in order to identify its putative target(s). This approach, combined with mass spectrometry, identified 18 potential candidates, all being serine or cysteine enzymes involved in <I>M. tb</I> lipid metabolism and/or in cell wall biosynthesis. Among them, Ag85A, CaeA, TesA, KasA and MetA have been reported as essential for <I>in vitro</I> growth of <I>M. tb</I> and/or its survival and persistence inside macrophages. Overall, our findings support the assumption that <B>OX</B> derivatives may represent a novel class of multi-target inhibitors leading to the arrest of <I>M. tb</I> growth through a cumulative inhibition of a large number of Ser- and Cys-containing enzymes involved in various important physiological processes.</P> <P><B>Highlights</B></P> <P> <UL> <LI> The OX analogs represent a novel class of multi-target inhibitors against <I>M. tb.</I> </LI> <LI> Some OX inhibit either extracellular, or both intra- and extracellular <I>M. tb</I> growth. </LI> <LI> These OXs are not toxic towards host macrophages. </LI> <LI> OX probes are attractive chemical tools to identify (Ser/Cys)-enzymes in living mycobacteria. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
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