Depletion of . GlmU from Infected Murine Lungs Effects the Clearance of the Pathogen

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The synthesis of the Mtb cell wall involves a cascade of reactions catalyzed by cytosolic and cell membrane-bound enzymes. The reaction catalyzed by GlmUMtb (an enzyme with acetyltransferase and uridyltransferase activities) generates UDP-GlcNAc, a central nucleotide-sugar building block of the cell wall. Apart from cell wall synthesis UDP-GlcNAc is an essential metabolite participating in other cellular processes including disaccharide linker and mycothiol biosynthesis. GlmUMtb shares very little sequence similarity with eukaryotic acetyltransferase and uridyltransferase enzymes. Many pathogens have alternative pathway(s) for foraging GlcNAc from the host. The present study was undertaken to see the effects of depleting GlmUMtb on pathogen survival in the host animal. We have generated a conditional gene replacement mutant of glmUMtb and find that depletion of GlmUMtb at any stage of bacterial growth or in mice infected with Mtb including a well-established infection, results in irreversible bacterial death due to perturbation of cell wall synthesis. We have developed a novel anti-GlmUMtb inhibitor (Oxa33), identified its binding site on GlmUMtb, and shown its specificity for GlmUMtb. The study demonstrates that GlmUMtb is a promising target for therapeutic intervention and Oxa33 can be pursued as a lead molecule.

Vyšlo v časopise: Depletion of . GlmU from Infected Murine Lungs Effects the Clearance of the Pathogen. PLoS Pathog 11(10): e32767. doi:10.1371/journal.ppat.1005235
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1005235

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