title: Rapid cytolysis of Mycobacterium tuberculosis by faropenem, an orally bioavailable β-lactam antibiotic.
abstract: Recent clinical studies indicate that meropenem, a β-lactam antibiotic, is a promising candidate for therapy of drug-resistant tuberculosis. However, meropenem is chemically unstable, requires frequent intravenous injection, and must be combined with a β-lactamase inhibitor (clavulanate) for optimal activity. Here, we report that faropenem, a stable and orally bioavailable β-lactam, efficiently kills Mycobacterium tuberculosis even in the absence of clavulanate. The target enzymes, L,D-transpeptidases, were inactivated 6- to 22-fold more efficiently by faropenem than by meropenem. Using a real-time assay based on quantitative time-lapse microscopy and microfluidics, we demonstrate the superiority of faropenem to the frontline antituberculosis drug isoniazid in its ability to induce the rapid cytolysis of single cells. Faropenem also showed superior activity against a cryptic subpopulation of nongrowing but metabolically active cells, which may correspond to the viable but nonculturable forms believed to be responsible for relapses following prolonged chemotherapy. These results identify faropenem to be a potential candidate for alternative therapy of drug-resistant tuberculosis.
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: Sorbonne Universités, UPMC Univ Paris 06, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Equipe 12, Paris, France Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France Open Collaborative Model for Tuberculosis Lead Optimisation (ORCHID) Consortium.
authors.forename: Vincent
authors.initials: V
authors.lastname: Dubée
authors.affiliation: Diseases of the Developing World (DDW), Tres Cantos Medicines Development Campus (TCMDC), GlaxoSmithKline, Madrid, Spain Open Collaborative Model for Tuberculosis Lead Optimisation (ORCHID) Consortium.
authors.forename: Lluis
authors.initials: L
authors.lastname: Ballell
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Equipe 12, Paris, France Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Cuinet
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Equipe 12, Paris, France Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France Open Collaborative Model for Tuberculosis Lead Optimisation (ORCHID) Consortium.
authors.forename: Jean-Emmanuel
authors.initials: JE
authors.lastname: Hugonnet
authors.affiliation: School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: François
authors.initials: F
authors.lastname: Signorino-Gelo
authors.affiliation: Diseases of the Developing World (DDW), Tres Cantos Medicines Development Campus (TCMDC), GlaxoSmithKline, Madrid, Spain Open Collaborative Model for Tuberculosis Lead Optimisation (ORCHID) Consortium david.a.barros@gsk.com.
authors.forename: David
authors.initials: D
authors.lastname: Barros
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Equipe 12, Paris, France Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France Open Collaborative Model for Tuberculosis Lead Optimisation (ORCHID) Consortium.
authors.forename: Michel
authors.initials: M
authors.lastname: Arthur
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
mesh_terms: D000995:Antitubercular Agents / Q000494:pharmacology*; D007538:Isoniazid / Q000494:pharmacology; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D010458:Peptidyl Transferases / Q000378:metabolism; D047090:beta-Lactams / Q000494:pharmacology*
chemical_list: D000995:Antitubercular Agents; D047090:beta-Lactams; D010458:Peptidyl Transferases; C107057:fropenem; D007538:Isoniazid