title: The changes in mycolic acid structures caused by hadC mutation have a dramatic effect on the virulence of Mycobacterium tuberculosis.
abstract: Understanding the molecular strategies used by Mycobacterium tuberculosis to invade and persist within the host is of paramount importance to tackle the tuberculosis pandemic. Comparative genomic surveys have revealed that hadC, encoding a subunit of the HadBC dehydratase, is mutated in the avirulent M. tuberculosis H37Ra strain. We show here that mutation or deletion of hadC affects the biosynthesis of oxygenated mycolic acids, substantially reducing their production level. Additionally, it causes the loss of atypical extra-long mycolic acids, demonstrating the involvement of HadBC in the late elongation steps of mycolic acid biosynthesis. These events have an impact on the morphotype, cording capacity and biofilm growth of the bacilli as well as on their sensitivity to agents such as rifampicin. Furthermore, deletion of hadC leads to a dramatic loss of virulence: an almost 4-log drop of the bacterial load in the lungs and spleens of infected immunodeficient mice. Both its unique function and importance for M. tuberculosis virulence make HadBC an attractive therapeutic target for tuberculosis drug development.
authors.affiliation: Département Tuberculose & Biologie des Infections, Institut de Pharmacologie et de Biologie Structurale - UMR5089, Centre National de la Recherche Scientifique, Toulouse, France.|Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, Université Paul Sabatier, Toulouse, France.
authors.forename: Nawel
authors.initials: N
authors.lastname: Slama
authors.affiliation: Département Tuberculose & Biologie des Infections, Institut de Pharmacologie et de Biologie Structurale - UMR5089, Centre National de la Recherche Scientifique, Toulouse, France.|Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, Université Paul Sabatier, Toulouse, France.
authors.forename: Stevie
authors.initials: S
authors.lastname: Jamet
authors.affiliation: Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics, Paris, France.
authors.forename: Wafa
authors.initials: W
authors.lastname: Frigui
authors.affiliation: Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics, Paris, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Pawlik
authors.affiliation: Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics, Paris, France.
authors.forename: Daria
authors.initials: D
authors.lastname: Bottai
authors.affiliation: Département Tuberculose & Biologie des Infections, Institut de Pharmacologie et de Biologie Structurale - UMR5089, Centre National de la Recherche Scientifique, Toulouse, France.|Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, Université Paul Sabatier, Toulouse, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Laval
authors.affiliation: Département Tuberculose & Biologie des Infections, Institut de Pharmacologie et de Biologie Structurale - UMR5089, Centre National de la Recherche Scientifique, Toulouse, France.|Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, Université Paul Sabatier, Toulouse, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Constant
authors.affiliation: Département Tuberculose & Biologie des Infections, Institut de Pharmacologie et de Biologie Structurale - UMR5089, Centre National de la Recherche Scientifique, Toulouse, France.|Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, Université Paul Sabatier, Toulouse, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Lemassu
authors.affiliation: Département Tuberculose & Biologie des Infections, Institut de Pharmacologie et de Biologie Structurale - UMR5089, Centre National de la Recherche Scientifique, Toulouse, France.|Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, Université Paul Sabatier, Toulouse, France.
authors.forename: Kaymeuang
authors.initials: K
authors.lastname: Cam
authors.affiliation: Département Tuberculose & Biologie des Infections, Institut de Pharmacologie et de Biologie Structurale - UMR5089, Centre National de la Recherche Scientifique, Toulouse, France.|Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, Université Paul Sabatier, Toulouse, France.
authors.forename: Mamadou
authors.initials: M
authors.lastname: Daffé
authors.affiliation: Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics, Paris, France.
authors.forename: Roland
authors.initials: R
authors.lastname: Brosch
authors.affiliation: Département Tuberculose & Biologie des Infections, Institut de Pharmacologie et de Biologie Structurale - UMR5089, Centre National de la Recherche Scientifique, Toulouse, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Eynard
authors.affiliation: Département Tuberculose & Biologie des Infections, Institut de Pharmacologie et de Biologie Structurale - UMR5089, Centre National de la Recherche Scientifique, Toulouse, France.|Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, Université Paul Sabatier, Toulouse, France.
authors.forename: Annaïk
authors.initials: A
authors.lastname: Quémard
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000494:pharmacology; D058491:Bacterial Load; D001426:Bacterial Proteins / Q000235:genetics* / Q000378:metabolism; D018441:Biofilms / Q000254:growth & development; D017353:Gene Deletion; D008168:Lung / Q000382:microbiology; D051379:Mice; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000737:chemistry / Q000201:enzymology / Q000235:genetics* / Q000472:pathogenicity*; D009171:Mycolic Acids / Q000737:chemistry* / Q000378:metabolism; D013154:Spleen / Q000382:microbiology; D014376:Tuberculosis / Q000382:microbiology*; D014774:Virulence / Q000235:genetics
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D009171:Mycolic Acids