title: Benzylidene acylhydrazides inhibit chlamydial growth in a type III secretion- and iron chelation-independent manner.
abstract: Chlamydiae are widespread Gram-negative pathogens of humans and animals. Salicylidene acylhydrazides, developed as inhibitors of type III secretion system (T3SS) in Yersinia spp., have an inhibitory effect on chlamydial infection. However, these inhibitors also have the capacity to chelate iron, and it is possible that their antichlamydial effects are caused by iron starvation. Therefore, we have explored the modification of salicylidene acylhydrazides with the goal to uncouple the antichlamydial effect from iron starvation. We discovered that benzylidene acylhydrazides, which cannot chelate iron, inhibit chlamydial growth. Biochemical and genetic analyses suggest that the derivative compounds inhibit chlamydiae through a T3SS-independent mechanism. Four single nucleotide polymorphisms were identified in a Chlamydia muridarum variant resistant to benzylidene acylhydrazides, but it may be necessary to segregate the mutations to differentiate their roles in the resistance phenotype. Benzylidene acylhydrazides are well tolerated by host cells and probiotic vaginal Lactobacillus species and are therefore of potential therapeutic value.
authors.affiliation: Department of Pharmacology, Rutgers University Robert Wood Johnson Medical School, Piscataway, New Jersey, USA Department of Pharmacology, Nantong University School of Pharmacy, Nantong, People's Republic of China.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Bao
authors.affiliation: Department of Clinical Microbiology, Umeå University, Umeå, Sweden.
authors.forename: Asa
authors.initials: A
authors.lastname: Gylfe
authors.affiliation: Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA.
authors.forename: Gail L
authors.initials: GL
authors.lastname: Sturdevant
authors.affiliation: Department of Pharmacology, Rutgers University Robert Wood Johnson Medical School, Piscataway, New Jersey, USA.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Gong
authors.affiliation: Department of Pharmacology, Rutgers University Robert Wood Johnson Medical School, Piscataway, New Jersey, USA.
authors.forename: Shuang
authors.initials: S
authors.lastname: Xu
authors.affiliation: Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA.
authors.forename: Harlan D
authors.initials: HD
authors.lastname: Caldwell
authors.affiliation: Department of Chemistry, Umeå University, Umeå, Sweden.
authors.forename: Mikael
authors.initials: M
authors.lastname: Elofsson
authors.affiliation: Department of Pharmacology, Rutgers University Robert Wood Johnson Medical School, Piscataway, New Jersey, USA huizhou.fan@rutgers.edu.
authors.forename: Huizhou
authors.initials: H
authors.lastname: Fan
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001597:Benzylidene Compounds / Q000494:pharmacology*; D023502:Chlamydia muridarum / Q000187:drug effects* / Q000254:growth & development*; D004252:DNA Mutational Analysis; D024881:Drug Resistance, Bacterial; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA
chemical_list: D000900:Anti-Bacterial Agents; D001597:Benzylidene Compounds