Département de chimie moléculaire

A review. Francisella tularensis is the etiol. agent of tularemia and a CDC class A biol. threat agent. Few antibiotic classes are currently useful in treating tularemia, including the aminoglycosides gentamicin and streptomycin, fluoroquinolones, and tetracyclines. However, treatment failures and relapses remain frequent and F. tularensis strains resistant to antibiotics have been easily selected in vitro. In this study, we evaluated the activity of new synthetic bis-indole derivs. against this pathogen. Min. inhibitory concns. (MICs) of four compds. (dcm01 to dcm04) were detd. for the ref. strains F. tularensis subsp. holarctica LVS NCTC10857, F. tularensis subsp. novicida CIP56.12 and F. philomiragia ATCC25015, and for 41 clin. strains of F. tularensis subsp. holarctica isolated in France. Minimal bactericidal concns. (MBCs) were detd. for the dcm02 and dcm04 compds. for the LVS and two clin. strains. Killing curves were also detd. for the same three strains exposed to dcm04. All tested bis-indole compds. were bacteriostatic against F. tularensis subsp. holarctica strains, with a MIC90 of 8 μg/mL for dcm01, dcm02, and dcm03, and 2 μg/mL for dcm04. Only one strain was resistant to both dcm01 and dcm03, with MICs ≥ 32 μg/mL. In contrast, F. tularensis subsp. novicida was resistant to all derivs. and F. philomiragia was only susceptible to dcm02 and dcm04, with MICs of 16 and 4 μg/mL, resp. MBC and killing curve expts. revealed significant bactericidal activity (i.e., 3-log redn. of the bacterial inoculum) of the dcm02 and dcm04 compds. only for the LVS strain. In conclusion, we have identified novel synthetic bis-indole compds. that are active against F. tularensis subsp. holarctica. They may be drug candidates for the development of new therapeutic alternatives for tularemia treatment. Their further characterization is needed, esp. identification of their bacterial targets.