Pre-clinical pharmacokinetics and anti-chlamydial activity of salicylidene acylhydrazide inhibitors of bacterial type III secretion - PubMed (original) (raw)

. 2012 Aug;65(8):397-404.

doi: 10.1038/ja.2012.43. Epub 2012 Jun 6.

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Free PMC article

Pre-clinical pharmacokinetics and anti-chlamydial activity of salicylidene acylhydrazide inhibitors of bacterial type III secretion

Tofeeq Ur-Rehman et al. J Antibiot (Tokyo). 2012 Aug.

Free PMC article

Abstract

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.

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Figures

Figure 1

Figure 1

Plasma and blood concentrations over time. (a) Plasma concentration for seven salicylidene acylhydrazides administered intraperitoneally in two cassettes (each compound 15–19 μg, 0.7–1 mg kg−1) to two mice per cassette. Filled symbols represent compounds in cassette 1 and open symbols cassette 2. ME0053 was included in both cassettes. Blood samples were collected 10, 30, 45, 60, 90 and 240 min after administration of compounds. Blood concentrations over time for (b) ME0177 after 1 mg (52–60 mg kg−1) dose and for (c) ME0192 after 0.5 mg (28–30 mg kg−1) dose administered intraperitoneally to seven mice per compound. Five mice were sampled at each time point, 10, 30, 60, 120, 180, 240, and 300 min after administration for ME0177 and 10, 30, 60, 120, 240, 480 and 720 min after administration of ME0192.

Figure 2

Figure 2

The number of inclusion forming unit (IFU) of C. trachomatis in vaginal cultures from mice treated intravaginally with ME0192 (open triangle, _n_=20) or vehicle without compound (filled circles, _n_=25) during the four week observation period after infection. The median IFU are indicated by horizontal lines and was 0 in the ME0192-treated group during the whole experiment.

Figure 3

Figure 3

Accumulation of the auto fluorescent compound ME0192 in _C. trachomatis-_infected HeLa cells. Chlamydia inclusions, indicated by arrows, can be distinguished by their morphology in nucleic acid staining (b) and (e) (SYTOX orange) and (h) (DAPI). (a–c) Cells incubated with ME0192. The blue fluorescent ME0192 accumulates in Chlamydia inclusions (a). (c) is a merge of (a) and (b). (d-f): Cells incubated with solvent (1% DMSO), only background in the blue channel (d). (f) is a merge of (d) and (e). (g–k) Immunostaining: green Chlamydia inclusions (g), DAPI (h), Evans blue staining of cells (i) and merge (k).

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