title: Cell division inhibitors with efficacy equivalent to isoniazid in the acute murine Mycobacterium tuberculosis infection model.
abstract: OBJECTIVE
  The increasing number of clinical strains resistant to one or more of the front-line TB drugs complicates the management of this disease. To develop next-generation benzimidazole-based FtsZ inhibitors with improved efficacy, we employed iterative optimization strategies based on whole bacteria potency, bactericidal activity, plasma and metabolic stability and in vivo efficacy studies.
  
  
  METHODS
  Candidate benzimidazoles were evaluated for potency against Mycobacterium tuberculosis H37Rv and select clinical strains, toxicity against Vero cells and compound stability in plasma and liver microsomes. The efficacy of lead compounds was assessed in the acute murine M. tuberculosis infection model via intraperitoneal and oral routes.
  
  
  RESULTS
  MICs of SB-P17G-A33, SB-P17G-A38 and SB-P17G-A42 for M. tuberculosis H37Rv and select clinical strains were 0.18-0.39 mg/L. SB-P17G-A38 and SB-P17G-A42 delivered at 50 mg/kg twice daily intraperitoneally or orally demonstrated efficacy in reducing the bacterial load by 5.7-6.3 log10 cfu in the lungs and 3.9-5.0 log10 cfu in the spleen. SB-P17G-A33 delivered at 50 mg/kg twice daily intraperitoneally or orally also reduced the bacterial load by 1.7-2.1 log10 cfu in the lungs and 2.5-3.4 log10 cfu in the spleen.
  
  
  CONCLUSIONS
  Next-generation benzimidazoles with excellent potency and efficacy against M. tuberculosis have been developed. This is the first report on benzimidazole-based FtsZ inhibitors showing an equivalent level of efficacy to isoniazid in an acute murine M. tuberculosis infection model.
authors.affiliation: Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523-1682, USA.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Knudson
authors.affiliation: Department of Chemistry, Stony Brook University, Stony Brook, NY 11794-3400, USA.
authors.forename: Divya
authors.initials: D
authors.lastname: Awasthi
authors.affiliation: Institute of Chemical Biology & Drug Discovery, Stony Brook University, Stony Brook, NY 11794-3400, USA.
authors.forename: Kunal
authors.initials: K
authors.lastname: Kumar
authors.affiliation: Sanofi-Aventis R&D, Infectious Disease Unit, 31036 Toulouse, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Carreau
authors.affiliation: Sanofi-Aventis R&D, Infectious Disease Unit, 31036 Toulouse, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Goullieux
authors.affiliation: Sanofi-Aventis R&D, Infectious Disease Unit, 31036 Toulouse, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Lagrange
authors.affiliation: Sanofi-Aventis R&D, Drug Disposition, 34184 Montpellier, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Vermet
authors.affiliation: Department of Chemistry, Stony Brook University, Stony Brook, NY 11794-3400, USA Institute of Chemical Biology & Drug Discovery, Stony Brook University, Stony Brook, NY 11794-3400, USA.
authors.forename: Iwao
authors.initials: I
authors.lastname: Ojima
authors.affiliation: Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523-1682, USA richard.slayden@colostate.edu.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Slayden
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000995:Antitubercular Agents / Q000008:administration & dosage* / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors; D001562:Benzimidazoles / Q000008:administration & dosage* / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors; D004195:Disease Models, Animal; D004355:Drug Stability; D008658:Inactivation, Metabolic; D007274:Injections, Intraperitoneal; D007538:Isoniazid / Q000008:administration & dosage* / Q000494:pharmacology; D051379:Mice; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D016896:Treatment Outcome; D014376:Tuberculosis / Q000188:drug therapy*; D014709:Vero Cells
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D001562:Benzimidazoles; D003598:Cytoskeletal Proteins; C071525:FtsZ protein, Bacteria; D007538:Isoniazid