Biosynthesis and transport of cell wall glycolipids in mycobacteria

Abstract

The genus Mycobacterium contains a number of medically important bacterial pathogens. The most important of these, M. tuberculosis, infects one third of the world's population and causes more than 2 million deaths each year. The unusual cell wall of mycobacteria contribute to the pathogenesis, host immune responses and inherent resistance of these bacilli to common antibiotics and antiseptics. The mycobacterial wall comprises macromolecular components (peptidoglycan, arabinogalactan and covalently linked mycolic acids) as well as free glycolipids, such as trehalose mycolates, phosphatidylinositol mannosides (PIMs) and lipoarabinomannan (LAM). While progress has been made in identifying enzymes involved in the synthesis of different cell wall components, little is known about the transport of precursors from the inner leaflet of the plasma membrane to the periplasmic space. Using a combination of transposon mutagenesis, genome wide bioinformatics searches and genetic studies in the related bacterium Corynebacterium glutamicum, we have identified genes that are essential for both the assembly and transport of mature PIMs, LAM and trehalose mycolates. These findings point to the presence of multimeric protein complexes that are involved in regulating flux of intermediates and balanced cell wall synthesis.