title: Combinations of β-Lactam Antibiotics Currently in Clinical Trials Are Efficacious in a DHP-I-Deficient Mouse Model of Tuberculosis Infection.
abstract: We report here a dehydropeptidase-deficient murine model of tuberculosis (TB) infection that is able to partially uncover the efficacy of marketed broad-spectrum β-lactam antibiotics alone and in combination. Reductions of up to 2 log CFU in the lungs of TB-infected mice after 8 days of treatment compared to untreated controls were obtained at blood drug concentrations and time above the MIC (T>MIC) below clinically achievable levels in humans. These findings provide evidence supporting the potential of β-lactams as safe and mycobactericidal components of new combination regimens against TB with or without resistance to currently used drugs.
authors.affiliation: Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain Open Collaborative Model for Tuberculosis Lead Optimisation (ORCHID) Consortium‡
authors.forename: Joaquín
authors.initials: J
authors.lastname: Rullas
authors.affiliation: School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne, Switzerland Open Collaborative Model for Tuberculosis Lead Optimisation (ORCHID) Consortium‡
authors.forename: Neeraj
authors.initials: N
authors.lastname: Dhar
authors.affiliation: School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne, Switzerland Open Collaborative Model for Tuberculosis Lead Optimisation (ORCHID) Consortium‡
authors.forename: John D
authors.initials: JD
authors.lastname: McKinney
authors.affiliation: Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain Open Collaborative Model for Tuberculosis Lead Optimisation (ORCHID) Consortium‡
authors.forename: Adolfo
authors.initials: A
authors.lastname: García-Pérez
authors.affiliation: Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain Open Collaborative Model for Tuberculosis Lead Optimisation (ORCHID) Consortium‡
authors.forename: Joël
authors.initials: J
authors.lastname: Lelievre
authors.affiliation: Open Collaborative Model for Tuberculosis Lead Optimisation (ORCHID) Consortium‡ Department of Medical Biochemistry, Stellenbosch University, Tygerberg, South Africa.
authors.forename: Andreas H
authors.initials: AH
authors.lastname: Diacon
authors.affiliation: Centre de Recherche des Cordeliers, LRMA, Equipe 12, Université Pierre et Marie Curie-Paris 6, UMR S 872, Paris, France Institut National de la Santé et de la Recherche Médicale (INSERM), U872, Paris, France Université Paris Descartes, Sorbonne Paris Cité, UMR S 872, Paris, France Open Collaborative Model for Tuberculosis Lead Optimisation (ORCHID) Consortium‡
authors.forename: Jean-Emmanuel
authors.initials: JE
authors.lastname: Hugonnet
authors.affiliation: Centre de Recherche des Cordeliers, LRMA, Equipe 12, Université Pierre et Marie Curie-Paris 6, UMR S 872, Paris, France Institut National de la Santé et de la Recherche Médicale (INSERM), U872, Paris, France Université Paris Descartes, Sorbonne Paris Cité, UMR S 872, Paris, France Open Collaborative Model for Tuberculosis Lead Optimisation (ORCHID) Consortium‡
authors.forename: Michel
authors.initials: M
authors.lastname: Arthur
authors.affiliation: Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain Open Collaborative Model for Tuberculosis Lead Optimisation (ORCHID) Consortium‡
authors.forename: Iñigo
authors.initials: I
authors.lastname: Angulo-Barturen
authors.affiliation: Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain Open Collaborative Model for Tuberculosis Lead Optimisation (ORCHID) Consortium‡
authors.forename: David
authors.initials: D
authors.lastname: Barros-Aguirre
authors.affiliation: Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain Open Collaborative Model for Tuberculosis Lead Optimisation (ORCHID) Consortium‡ lluis.p.ballell@gsk.com.
authors.forename: Lluís
authors.initials: L
authors.lastname: Ballell
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D004150:Dipeptidases / Q000172:deficiency*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination / Q000379:methods; D058851:GPI-Linked Proteins / Q000172:deficiency; D008168:Lung / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008826:Microbial Sensitivity Tests / Q000379:methods; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D012141:Respiratory Tract Infections / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000378:metabolism / Q000382:microbiology; D014376:Tuberculosis / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology; D047090:beta-Lactams / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D058851:GPI-Linked Proteins; D047090:beta-Lactams; D004150:Dipeptidases; C549872:dipeptidase 1