title: Delayed bactericidal response of Mycobacterium tuberculosis to bedaquiline involves remodelling of bacterial metabolism.
abstract: Bedaquiline (BDQ), an ATP synthase inhibitor, is the first drug to be approved for treatment of multidrug-resistant tuberculosis in decades. Though BDQ has shown excellent efficacy in clinical trials, its early bactericidal activity during the first week of chemotherapy is minimal. Here, using microfluidic devices and time-lapse microscopy of Mycobacterium tuberculosis, we confirm the absence of significant bacteriolytic activity during the first 3-4 days of exposure to BDQ. BDQ-induced inhibition of ATP synthesis leads to bacteriostasis within hours after drug addition. Transcriptional and proteomic analyses reveal that M. tuberculosis responds to BDQ by induction of the dormancy regulon and activation of ATP-generating pathways, thereby maintaining bacterial viability during initial drug exposure. BDQ-induced bacterial killing is significantly enhanced when the mycobacteria are grown on non-fermentable energy sources such as lipids (impeding ATP synthesis via glycolysis). Our results show that BDQ exposure triggers a metabolic remodelling in mycobacteria, thereby enabling transient bacterial survival.
authors.affiliation: Infectious diseases and vaccines therapeutic area, Janssen Research & Development, Johnson & Johnson Pharmaceuticals, Turnhoutseweg 30, 2340 Beerse, Belgium.
authors.forename: Anil
authors.initials: A
authors.lastname: Koul
authors.affiliation: Infectious diseases and vaccines therapeutic area, Janssen Research & Development, Johnson & Johnson Pharmaceuticals, Turnhoutseweg 30, 2340 Beerse, Belgium.
authors.forename: Luc
authors.initials: L
authors.lastname: Vranckx
authors.affiliation: Swiss Federal Institute of Technology in Lausanne (EPFL), School of Life Sciences, 1015 Lausanne, Switzerland.
authors.forename: Neeraj
authors.initials: N
authors.lastname: Dhar
authors.affiliation: CREATe, Janssen Research & Development, Johnson & Johnson Pharmaceuticals, Turnhoutseweg 30, 2340 Beerse, Belgium.
authors.forename: Hinrich W H
authors.initials: HW
authors.lastname: Göhlmann
authors.affiliation: Swiss Federal Institute of Technology in Lausanne (EPFL), School of Life Sciences, 1015 Lausanne, Switzerland.
authors.forename: Emre
authors.initials: E
authors.lastname: Özdemir
authors.affiliation: CREATe, Janssen Research & Development, Johnson & Johnson Pharmaceuticals, Turnhoutseweg 30, 2340 Beerse, Belgium.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Neefs
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, Campusvej 55, DK-5230 Odense M, Denmark.
authors.forename: Melanie
authors.initials: M
authors.lastname: Schulz
authors.affiliation: Department of Molecular Cell Biology, AIMMS, VU University Amsterdam, De Boelelaan 1085, 1081 HV Amsterdam, The Netherlands.
authors.forename: Ping
authors.initials: P
authors.lastname: Lu
authors.affiliation: Alphalyse A/S, Unsbjergvej 4, DK-5220 Odense SØ, Denmark.
authors.forename: Ejvind
authors.initials: E
authors.lastname: Mørtz
authors.affiliation: Swiss Federal Institute of Technology in Lausanne (EPFL), School of Life Sciences, 1015 Lausanne, Switzerland.
authors.forename: John D
authors.initials: JD
authors.lastname: McKinney
authors.affiliation: Infectious diseases and vaccines therapeutic area, Janssen Research & Development, Johnson & Johnson Pharmaceuticals, Turnhoutseweg 30, 2340 Beerse, Belgium.
authors.forename: Koen
authors.initials: K
authors.lastname: Andries
authors.affiliation: Department of Molecular Cell Biology, AIMMS, VU University Amsterdam, De Boelelaan 1085, 1081 HV Amsterdam, The Netherlands.
authors.forename: Dirk
authors.initials: D
authors.lastname: Bald
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000995:Antitubercular Agents / Q000494:pharmacology; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D064687:Diarylquinolines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D020869:Gene Expression Profiling / Q000379:methods; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects*; D006019:Glycolysis / Q000187:drug effects*; D050296:Microbial Viability / Q000187:drug effects / Q000235:genetics; D046210:Microfluidic Analytical Techniques; D008856:Microscopy, Fluorescence; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D020543:Proteome / Q000235:genetics / Q000378:metabolism; D040901:Proteomics / Q000379:methods; D020133:Reverse Transcriptase Polymerase Chain Reaction; D059010:Single-Cell Analysis / Q000379:methods; D013997:Time Factors; D059008:Time-Lapse Imaging
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D064687:Diarylquinolines; D020543:Proteome; C493870:bedaquiline; D000255:Adenosine Triphosphate