title: A 2-pyridone-amide inhibitor targets the glucose metabolism pathway of Chlamydia trachomatis.
abstract: In a screen for compounds that inhibit infectivity of the obligate intracellular pathogen Chlamydia trachomatis, we identified the 2-pyridone amide KSK120. A fluorescent KSK120 analogue was synthesized and observed to be associated with the C. trachomatis surface, suggesting that its target is bacterial. We isolated KSK120-resistant strains and determined that several resistance mutations are in genes that affect the uptake and use of glucose-6-phosphate (G-6P). Consistent with an effect on G-6P metabolism, treatment with KSK120 blocked glycogen accumulation. Interestingly, KSK120 did not affect Escherichia coli or the host cell. Thus, 2-pyridone amides may represent a class of drugs that can specifically inhibit C. trachomatis infection.
  
  
  OBJECTIVE
  Chlamydia trachomatis is a bacterial pathogen of humans that causes a common sexually transmitted disease as well as eye infections. It grows only inside cells of its host organism, within a parasitophorous vacuole termed the inclusion. Little is known, however, about what bacterial components and processes are important for C. trachomatis cellular infectivity. Here, by using a visual screen for compounds that affect bacterial distribution within the chlamydial inclusion, we identified the inhibitor KSK120. As hypothesized, the altered bacterial distribution induced by KSK120 correlated with a block in C. trachomatis infectivity. Our data suggest that the compound targets the glucose-6-phosphate (G-6P) metabolism pathway of C. trachomatis, supporting previous indications that G-6P metabolism is critical for C. trachomatis infectivity. Thus, KSK120 may be a useful tool to study chlamydial glucose metabolism and has the potential to be used in the treatment of C. trachomatis infections.
authors.affiliation: Department of Molecular Biology, Umeå University, Umeå, Sweden Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University, Umeå, Sweden Umeå Centre for Microbial Research (UCMR), Umeå University, Umeå, Sweden Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California, USA.
authors.forename: Patrik
authors.initials: P
authors.lastname: Engström
authors.affiliation: Umeå Centre for Microbial Research (UCMR), Umeå University, Umeå, Sweden Department of Chemistry, Umeå University, Umeå, Sweden.
authors.forename: K Syam
authors.initials: KS
authors.lastname: Krishnan
authors.affiliation: Department of Molecular Genetics and Microbiology, Center for Microbial Pathogenesis, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Bidong D
authors.initials: BD
authors.lastname: Ngyuen
authors.affiliation: Umeå Centre for Microbial Research (UCMR), Umeå University, Umeå, Sweden Department of Chemistry, Umeå University, Umeå, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Chorell
authors.affiliation: Department of Molecular Biology, Umeå University, Umeå, Sweden Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University, Umeå, Sweden Umeå Centre for Microbial Research (UCMR), Umeå University, Umeå, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Normark
authors.affiliation: Department of Molecular Biology, Umeå University, Umeå, Sweden.
authors.forename: Jim
authors.initials: J
authors.lastname: Silver
authors.affiliation: Department of Molecular Genetics and Microbiology, Center for Microbial Pathogenesis, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Bastidas
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Welch
authors.affiliation: Department of Molecular Microbiology and Center for Women's Infectious Disease Research, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Hultgren
authors.affiliation: Department of Molecular Biology, Umeå University, Umeå, Sweden Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University, Umeå, Sweden Umeå Centre for Microbial Research (UCMR), Umeå University, Umeå, Sweden.
authors.forename: Hans
authors.initials: H
authors.lastname: Wolf-Watz
authors.affiliation: Department of Molecular Genetics and Microbiology, Center for Microbial Pathogenesis, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Raphael H
authors.initials: RH
authors.lastname: Valdivia
authors.affiliation: Umeå Centre for Microbial Research (UCMR), Umeå University, Umeå, Sweden Department of Chemistry, Umeå University, Umeå, Sweden Fredrik.almqvist@chem.umu.se Sven.bergstrom@molbiol.umu.se.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Almqvist
authors.affiliation: Department of Molecular Biology, Umeå University, Umeå, Sweden Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University, Umeå, Sweden Umeå Centre for Microbial Research (UCMR), Umeå University, Umeå, Sweden Fredrik.almqvist@chem.umu.se Sven.bergstrom@molbiol.umu.se.
authors.forename: Sven
authors.initials: S
authors.lastname: Bergström
mesh_terms: D050260:Carbohydrate Metabolism / Q000187:drug effects*; D002692:Chlamydia trachomatis / Q000187:drug effects* / Q000378:metabolism*; D004252:DNA Mutational Analysis; D024881:Drug Resistance, Bacterial; D004791:Enzyme Inhibitors / Q000378:metabolism*; D004926:Escherichia coli / Q000187:drug effects; D019298:Glucose-6-Phosphate / Q000378:metabolism*; D006367:HeLa Cells / Q000187:drug effects; D006801:Humans; D009154:Mutation; D011728:Pyridones / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D011728:Pyridones; D019298:Glucose-6-Phosphate; C017679:2-hydroxypyridine