title: The virulence-associated two-component PhoP-PhoR system controls the biosynthesis of polyketide-derived lipids in Mycobacterium tuberculosis.
abstract: Two-component regulatory signal transduction systems are important elements of the adaptative response of prokaryotes to a variety of environmental stimuli. Disruption of PhoP-PhoR in Mycobacterium tuberculosis dramatically attenuates virulence, implying that this system directly and/or indirectly coordinates the expression of important virulence factors whose identity remains to be established. Interestingly, in knockingout the PhoP-PhoR two-component system in M. tuberculosis Mt103, dramatic changes in the colonial morphology, cording properties, and reactivity of the mutant strain to the basic dye neutral red, all intrinsic properties of tubercle bacilli known to correlate with virulence, were noted. Because deficiencies in the ability of the mutant to form serpentine cords and stain with the dye are likely the results of alterations of its cell envelope composition, we undertook to analyze the lipid content of phoP and phoP-phoR mutants constructed in two different strains of M. tuberculosis. Our results indicate that PhoP coordinately and positively regulates the synthesis of methyl-branched fatty acid-containing acyltrehaloses known to be restricted to pathogenic species of the M. tuberculosis complex, namely diacyltrehaloses, polyacyltrehaloses, and sulfolipids. Evidence is also provided that PhoP but not PhoR is required for the production of these lipids. This work represents an important step toward the functional characterization of PhoP-PhoR and the understanding of complex lipid synthesis in M. tuberculosis.
authors.affiliation: Departamento de Microbiología, Medicina Preventiva y Salud Pública, Universidad de Zaragoza, C/Domingo Miral sin numero, 50009 Zaragoza, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Gonzalo Asensio
authors.forename: Catarina
authors.initials: C
authors.lastname: Maia
authors.forename: Nadia L
authors.initials: NL
authors.lastname: Ferrer
authors.forename: Nathalie
authors.initials: N
authors.lastname: Barilone
authors.forename: Françoise
authors.initials: F
authors.lastname: Laval
authors.forename: Carlos Yesid
authors.initials: CY
authors.lastname: Soto
authors.forename: Nathalie
authors.initials: N
authors.lastname: Winter
authors.forename: Mamadou
authors.initials: M
authors.lastname: Daffé
authors.forename: Brigitte
authors.initials: B
authors.lastname: Gicquel
authors.forename: Carlos
authors.initials: C
authors.lastname: Martín
authors.forename: Mary
authors.initials: M
authors.lastname: Jackson
mesh_terms: D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D008055:Lipids / Q000096:biosynthesis*; D018942:Macrolides / Q000378:metabolism; D016296:Mutagenesis; D009169:Mycobacterium tuberculosis / Q000201:enzymology* / Q000378:metabolism / Q000472:pathogenicity*; D010957:Plasmids; D016133:Polymerase Chain Reaction; D011494:Protein Kinases / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D014774:Virulence
chemical_list: D001426:Bacterial Proteins; D008055:Lipids; D018942:Macrolides; D011994:Recombinant Proteins; C061279:PhoR protein, Bacteria; C061064:PhoP protein, Bacteria; D011494:Protein Kinases