title: Mutations in hemG mediate resistance to salicylidene acylhydrazides, demonstrating a novel link between protoporphyrinogen oxidase (HemG) and Chlamydia trachomatis infectivity.
abstract: Salicylidene acylhydrazides (SAHs) inhibit the type III secretion system (T3S) of Yersinia and other Gram-negative bacteria. In addition, SAHs restrict the growth and development of Chlamydia species. However, since the inhibition of Chlamydia growth by SAH is suppressed by the addition of excess iron and since SAHs have an iron-chelating capacity, their role as specific T3S inhibitors is unclear. We investigated here whether SAHs exhibit a function on C. trachomatis that goes beyond iron chelation. We found that the iron-saturated SAH INP0341 (IS-INP0341) specifically affects C. trachomatis infectivity with reduced generation of infectious elementary body (EB) progeny. Selection and isolation of spontaneous SAH-resistant mutant strains revealed that mutations in hemG suppressed the reduced infectivity caused by IS-INP0341 treatment. Structural modeling of C. trachomatis HemG predicts that the acquired mutations are located in the active site of the enzyme, suggesting that IS-INP0341 inhibits this domain of HemG and that protoporphyrinogen oxidase (HemG) and heme metabolism are important for C. trachomatis infectivity.
authors.affiliation: Department of Molecular Biology, Laboratory for Molecular Infection Medicine, Sweden.
authors.forename: Patrik
authors.initials: P
authors.lastname: Engström
authors.forename: Bidong D
authors.initials: BD
authors.lastname: Nguyen
authors.forename: Johan
authors.initials: J
authors.lastname: Normark
authors.forename: Ingela
authors.initials: I
authors.lastname: Nilsson
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Bastidas
authors.forename: Asa
authors.initials: A
authors.lastname: Gylfe
authors.forename: Mikael
authors.initials: M
authors.lastname: Elofsson
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Fields
authors.forename: Raphael H
authors.initials: RH
authors.lastname: Valdivia
authors.forename: Hans
authors.initials: H
authors.lastname: Wolf-Watz
authors.forename: Sven
authors.initials: S
authors.lastname: Bergström
mesh_terms: D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D020134:Catalytic Domain; D002692:Chlamydia trachomatis / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics* / Q000472:pathogenicity; D024881:Drug Resistance, Bacterial; D006367:HeLa Cells; D006418:Heme / Q000378:metabolism; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology*; D007501:Iron / Q000378:metabolism / Q000494:pharmacology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D050768:Protoporphyrinogen Oxidase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D006834:Hydrazines; C541377:INP 0341; D006418:Heme; D007501:Iron; D050768:Protoporphyrinogen Oxidase