000202287 001__ 202287
000202287 005__ 20181203023629.0
000202287 0247_ $$2doi$$a10.1128/Jb.01346-13
000202287 022__ $$a0021-9193
000202287 02470 $$2ISI$$a000341237500009
000202287 037__ $$aARTICLE
000202287 245__ $$aThe Phosphatidyl-myo-Inositol Mannosyltransferase PimA Is Essential for Mycobacterium tuberculosis Growth In Vitro and In Vivo
000202287 260__ $$bAmer Soc Microbiology$$c2014$$aWashington
000202287 269__ $$a2014
000202287 300__ $$a11
000202287 336__ $$aJournal Articles
000202287 520__ $$aThe cell envelope of Mycobacterium tuberculosis contains glycans and lipids of peculiar structure that play prominent roles in the biology and pathogenesis of tuberculosis. Consequently, the chemical structure and biosynthesis of the cell wall have been intensively investigated in order to identify novel drug targets. Here, we validate that the function of phosphatidyl-myo-inositol mannosyltransferase PimA is vital for M. tuberculosis in vitro and in vivo. PimA initiates the biosynthesis of phosphatidyl-myo-inositol mannosides by transferring a mannosyl residue from GDP-Man to phosphatidyl-myo-inositol on the cytoplasmic side of the plasma membrane. To prove the essential nature of pimA in M. tuberculosis, we constructed a pimA conditional mutant by using the TetR-Pip off system and showed that downregulation of PimA expression causes bactericidality in batch cultures. Consistent with the biochemical reaction catalyzed by PimA, this phenotype was associated with markedly reduced levels of phosphatidyl-myo-inositol dimannosides, essential structural components of the mycobacterial cell envelope. In addition, the requirement of PimA for viability was clearly demonstrated during macrophage infection and in two different mouse models of infection, where a dramatic decrease in viable counts was observed upon silencing of the gene. Notably, depletion of PimA resulted in complete clearance of the mouse lungs during both the acute and chronic phases of infection. Altogether, the experimental data highlight the importance of the phosphatidyl-myo-inositol mannoside biosynthetic pathway for M. tuberculosis and confirm that PimA is a novel target for future drug discovery programs.
000202287 700__ $$uUniv Padua, Dept Mol Med, Padua, Italy$$aBoldrin, Francesca
000202287 700__ $$uEcole Polytech Fed Lausanne, Global Hlth Inst, Lausanne, Switzerland$$aVentura, Marcello
000202287 700__ $$uUniv Padua, Dept Mol Med, Padua, Italy$$aDegiacomi, Giulia
000202287 700__ $$uAstraZeneca India Pvt Ltd, Bangalore, Karnataka, India$$aRavishankar, Sudha
000202287 700__ $$0244366$$g179660$$uEcole Polytech Fed Lausanne, Global Hlth Inst, Lausanne, Switzerland$$aSala, Claudia
000202287 700__ $$uComenius Univ, Fac Nat Sci, Dept Biochem, Bratislava, Slovakia$$aSvetlikova, Zuzana
000202287 700__ $$uAstraZeneca India Pvt Ltd, Bangalore, Karnataka, India$$aAmbady, Anisha
000202287 700__ $$uEcole Polytech Fed Lausanne, Global Hlth Inst, Lausanne, Switzerland$$aDhar, Neeraj
000202287 700__ $$uComenius Univ, Fac Nat Sci, Dept Biochem, Bratislava, Slovakia$$aKordulakova, Jana
000202287 700__ $$0244372$$g190482$$uEcole Polytech Fed Lausanne, Global Hlth Inst, Lausanne, Switzerland$$aZhang, Ming
000202287 700__ $$uUniv Padua, Dept Mol Med, Padua, Italy$$aSerafini, Agnese
000202287 700__ $$uAstraZeneca India Pvt Ltd, Bangalore, Karnataka, India$$aVishwas, V. G.
000202287 700__ $$uEcole Polytech Fed Lausanne, Global Hlth Inst, Lausanne, Switzerland$$aKolly, Gaelle S.
000202287 700__ $$uAstraZeneca India Pvt Ltd, Bangalore, Karnataka, India$$aKumar, Naveen
000202287 700__ $$uUniv Padua, Dept Mol Med, Padua, Italy$$aPalu, Giorgio
000202287 700__ $$uUniv Basque Country, Ctr Mixto, CSIC, Unidad Biofis,Euskal Herriko Unibertsitatea, Bizkaia, Spain$$aGuerin, Marcelo E.
000202287 700__ $$uComenius Univ, Fac Nat Sci, Dept Biochem, Bratislava, Slovakia$$aMikusova, Katarina
000202287 700__ $$g177247$$uEcole Polytech Fed Lausanne, Global Hlth Inst, Lausanne, Switzerland$$aCole, Stewart T.$$0243892
000202287 700__ $$aManganelli, Riccardo$$uUniv Padua, Dept Mol Med, Padua, Italy
000202287 773__ $$j196$$tJournal Of Bacteriology$$k19$$q3441-3451
000202287 909C0 $$xU11742$$0252302$$pUPCOL
000202287 909CO $$pSV$$particle$$ooai:infoscience.tind.io:202287
000202287 917Z8 $$x217823
000202287 937__ $$aEPFL-ARTICLE-202287
000202287 973__ $$rREVIEWED$$sPUBLISHED$$aEPFL
000202287 980__ $$aARTICLE