title: Comparative metabolic profiling of mce1 operon mutant vs wild-type Mycobacterium tuberculosis strains.
abstract: Mycobacterium tuberculosis disrupted in a 13-gene operon (mce1) accumulates free mycolic acids (FM) in its cell wall and causes accelerated death in mice. Here, to more comprehensively analyze differences in their cell wall lipid composition, we used an untargeted metabolomics approach to compare the lipid profiles of wild-type and mce1 operon mutant strains. By liquid chromatography-mass spectrometry, we identified >400 distinct lipids significantly altered in the mce1 mutant compared to wild type. These lipids included decreased levels of saccharolipids and glycerophospholipids, and increased levels of alpha-, methoxy- and keto mycolic acids (MA), and hydroxyphthioceranic acid. The mutant showed reduced expression of mmpL8, mmpL10, stf0, pks2 and papA2 genes involved in transport and metabolism of lipids recognized to induce proinflammatory response; these lipids were found to be decreased in the mutant. In contrast, the transcripts of mmpL3, fasI, kasA, kasB, acpM and RV3451 involved in MA transport and metabolism increased; MA inhibits inflammatory response in macrophages. Since the mce1 operon is known to be regulated in intracellular M. tuberculosis, we speculate that the differences we observed in cell wall lipid metabolism and composition may affect host response to M. tuberculosis infection and determine the clinical outcome of such an infection.
authors: Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, CA 94720, USA.
authors: Adriano
authors: A
authors: Queiroz
authors: Program in Metabolic Biology, Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA 94720, USA.
authors: Daniel
authors: D
authors: Medina-Cleghorn
authors: Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, CA 94720, USA.
authors: Olivera
authors: O
authors: Marjanovic
authors: Program in Metabolic Biology, Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA 94720, USA.
authors: Daniel K
authors: DK
authors: Nomura
authors: Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, CA 94720, USA lwriley@berkeley.edu.
authors: Lee W
authors: LW
authors: Riley
mesh_terms: D001426:Bacterial Proteins / Q000235:genetics*; D002853:Chromatography, Liquid; D020869:Gene Expression Profiling; D008055:Lipids / Q000032:analysis*; D013058:Mass Spectrometry; D053858:Metabolic Networks and Pathways / Q000235:genetics; D055442:Metabolome; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000737:chemistry* / Q000235:genetics; D009876:Operon
chemical_list: D001426:Bacterial Proteins; D008055:Lipids; C473802:mammalian cell entry protein Mce1A, Mycobacterium tuberculosis
keywords: M. tuberculosis; lipidomics; mce1 operon