title: A small-molecule inhibitor of the bacterial type III secretion system protects against in vivo infection with Citrobacter rodentium.
abstract: The type III secretion system (T3SS) is highly conserved in many Gram-negative pathogenic bacteria and functions as an injector of bacterial proteins (effectors) into host cells. T3SSs are involved in establishing disease processes, but this machinery is not essential for bacterial growth or homeostasis. Thus, T3SS is expected to be a candidate therapeutic target, and inhibitors of T3SSs could potentially reduce virulence without causing bacterial death, thereby avoiding any subsequent development of resistance. We identified a linear polyketide compound, aurodox, as a specific T3SS inhibitor from the culture broth of Streptomyces sp. using a screening system for the T3SS-mediated hemolysis of enteropathogenic Escherichia coli (EPEC) established by our group. Aurodox strongly inhibited T3SS-mediated hemolysis with an IC(50) value of 1.5 μg ml(-1) without affecting bacterial growth in liquid media. We also demonstrated that aurodox specifically inhibits the secretion of type III-secreted proteins such as EspB, EspF and Map, without affecting the expression of the housekeeping protein GroEL. Furthermore, an in vivo infection study using mice clearly indicated that the administration of aurodox allowed the mice to survive a lethal dose of Citrobactor rodentium, a model bacterium for human pathogens such as EPEC. Thus, our in vivo study directly demonstrated for the first time that this putative T3SS inhibitor can be applied as a novel class of anti-infective agents.
authors.affiliation: Department of Drug Discovery Sciences, Infection Control and Immunology, Kitasato Institute for Life Sciences, Graduate School of Infection Control Sciences, Kitasato University, Tokyo, Japan.
authors.forename: Kyota
authors.initials: K
authors.lastname: Kimura
authors.forename: Masato
authors.initials: M
authors.lastname: Iwatsuki
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nagai
authors.forename: Atsuko
authors.initials: A
authors.lastname: Matsumoto
authors.forename: Yoko
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Kazuro
authors.initials: K
authors.lastname: Shiomi
authors.forename: Satoshi
authors.initials: S
authors.lastname: Omura
authors.forename: Akio
authors.initials: A
authors.lastname: Abe
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use*; D000899:Aurodox / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D044082:Citrobacter rodentium / Q000187:drug effects*; D004353:Drug Evaluation, Preclinical; D004756:Enterobacteriaceae Infections / Q000188:drug therapy*; D004926:Escherichia coli / Q000187:drug effects; D005260:Female; D006461:Hemolysis / Q000187:drug effects; D020128:Inhibitory Concentration 50; D026901:Membrane Transport Proteins / Q000378:metabolism*; D051379:Mice; D013302:Streptomyces / Q000378:metabolism; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D026901:Membrane Transport Proteins; D000899:Aurodox