Pre-clinical pharmacokinetics and anti-chlamydial activity of salicylidene acylhydrazide inhibitors of bacterial type III secretion.
Salicylidene acylhydrazides belong to a class of compounds shown to inhibit bacterial type III secretion (T3S) in pathogenic Gram-negative bacteria. This class of compounds also inhibits growth and replication of Chlamydiae, strict intracellular bacteria that possess a T3S system. In this study a library of 58 salicylidene acylhydrazides was screened to identify inhibitors of Chlamydia growth. Compounds inhibiting growth of both Chlamydia trachomatis and Chlamydophila pneumoniae were tested for cell toxicity and seven compounds were selected for preliminary pharmacokinetic analysis in mice using cassette dosing. Two compounds, ME0177 and ME0192, were further investigated by individual pharmacokinetic analysis. Compound ME0177 had a relatively high peak plasma concentration (C(max)) and area under curve and therefore may be considered for systemic treatment of Chlamydia infections. The other compound, ME0192, had poor pharmacokinetic properties but the highest anti-chlamydial activity in vitro and therefore was tested for topical treatment in a mouse vaginal infection model. ME0192 administered vaginally significantly reduced the infectious burden of C. trachomatis and the number of infected mice.
Department of Chemistry, Umeå University, Sweden.
Tofeeq
T
Ur-Rehman
Anatoly
A
Slepenkin
Hencelyn
H
Chu
Anders
A
Blomgren
Markus K
MK
Dahlgren
Caroline E
CE
Zetterström
Ellena M
EM
Peterson
Mikael
M
Elofsson
Asa
A
Gylfe
D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D019540:Area Under Curve; D002470:Cell Survival / Q000187:drug effects; D002690:Chlamydia Infections / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology; D002692:Chlamydia trachomatis / Q000187:drug effects* / Q000254:growth & development; D016993:Chlamydophila pneumoniae / Q000187:drug effects* / Q000254:growth & development; D005260:Female; D006367:HeLa Cells; D006801:Humans; D006834:Hydrazines / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests
D000900:Anti-Bacterial Agents; D006834:Hydrazines