title: Effects of Lipid-Lowering Drugs on Vancomycin Susceptibility of Mycobacteria.
abstract: Tuberculosis is still a cause of major concern, partly due to the emergence of multidrug-resistant strains. New drugs are therefore needed. Vancomycin can target mycobacteria with cell envelope deficiency. In this study, we used a vancomycin susceptibility assay to detect drugs hampering lipid synthesis in Mycobacterium bovis BCG and in Mycobacterium tuberculosis We tested three drugs already used to treat human obesity: tetrahydrolipstatin (THL), simvastatin, and fenofibrate. Only vancomycin and THL were able to synergize on M. bovis BCG and on M. tuberculosis, although mycobacteria could also be inhibited by simvastatin alone. Lipid analysis allowed us to identify several lipid modifications in M. tuberculosis H37Rv treated with those drugs. THL treatment mainly reduced the phthiocerol dimycocerosate (PDIM) content in the mycobacterial cell wall, providing an explanation for the synergy, since PDIM deficiency has been related to vancomycin susceptibility. Proteomic analysis suggested that bacteria treated with THL, in contrast to bacteria treated with simvastatin, tried to recover, inducing, among other reactions, lipid synthesis. The combination of THL and vancomycin should be considered a promising solution in developing new strategies to treat multidrug-resistant tuberculosis.
authors: Université Libre de Bruxelles (ULB), Unit of Pharmaceutical Microbiology and Hygiene, Brussels, Belgium.
authors: Céline
authors: C
authors: Rens
authors: Institute of Pharmacology and Structural Biology, University of Toulouse, CNRS, University Paul Sabatier (UMR 5089), Department of Tuberculosis and Infection Biology, Toulouse Cedex 04, France.
authors: Françoise
authors: F
authors: Laval
authors: Institute of Pharmacology and Structural Biology, University of Toulouse, CNRS, University Paul Sabatier (UMR 5089), Department of Tuberculosis and Infection Biology, Toulouse Cedex 04, France.
authors: Mamadou
authors: M
authors: Daffé
authors: Laboratory of Bacteriology, Department of Microbiology, Hôpital Erasme, Université Libre de Bruxelles (ULB), Brussels, Belgium.
authors: Olivier
authors: O
authors: Denis
authors: Institut Pasteur de Lille, Université de Lille, CNRS, INSERM, CHU Lille, U1019-UMR 8204, Center for Infection and Immunity of Lille, Lille, France.
authors: Rosangela
authors: R
authors: Frita
authors: Institut Pasteur de Lille, Université de Lille, CNRS, INSERM, CHU Lille, U1019-UMR 8204, Center for Infection and Immunity of Lille, Lille, France.
authors: Alain
authors: A
authors: Baulard
authors: Department of Proteomics and Microbiology, University of Mons, Mons, Belgium.
authors: Ruddy
authors: R
authors: Wattiez
authors: Université Libre de Bruxelles (ULB), Unit of Pharmaceutical Microbiology and Hygiene, Brussels, Belgium.
authors: Philippe
authors: P
authors: Lefèvre
authors: Université Libre de Bruxelles (ULB), Unit of Pharmaceutical Microbiology and Hygiene, Brussels, Belgium vfontain@ulb.ac.be.
authors: Véronique
authors: 0000-0001-7588-5462
authors: V
authors: Fontaine
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000995:Antitubercular Agents / Q000494:pharmacology; D004357:Drug Synergism; D011345:Fenofibrate / Q000494:pharmacology; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D007783:Lactones / Q000494:pharmacology; D008563:Membrane Lipids / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D009163:Mycobacterium bovis / Q000187:drug effects*; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000378:metabolism; D000077403:Orlistat; D019821:Simvastatin / Q000494:pharmacology; D014640:Vancomycin / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D000995:Antitubercular Agents; D000960:Hypolipidemic Agents; D007783:Lactones; D008563:Membrane Lipids; D014640:Vancomycin; D000077403:Orlistat; D019821:Simvastatin; D011345:Fenofibrate