The Phosphatidyl-myo-Inositol Mannosyltransferase PimA Is Essential for Mycobacterium tuberculosis Growth In Vitro and In Vivo

摘要: The cell envelope of Mycobacterium tuberculosis contains glycans and lipids peculiar structure that play prominent roles in the biology pathogenesis tuberculosis. Consequently, chemical biosynthesis wall have been intensively investigated order to identify novel drug targets. Here, we validate function phosphatidyl-myo-inositol mannosyltransferase PimA is vital for M. vitro vivo. initiates mannosides by transferring a mannosyl residue from GDP-Man on cytoplasmic side plasma membrane. To prove essential nature pimA tuberculosis, constructed conditional mutant using TetR-Pip off system showed downregulation expression causes bactericidality batch cultures. Consistent with biochemical reaction catalyzed PimA, this phenotype was associated markedly reduced levels dimannosides, structural components mycobacterial envelope. In addition, requirement viability clearly demonstrated during macrophage infection two different mouse models infection, where dramatic decrease viable counts observed upon silencing gene. Notably, depletion resulted complete clearance lungs both acute chronic phases infection. Altogether, experimental data highlight importance mannoside biosynthetic pathway confirm target future discovery programs.