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Nat Commun. 2014 Feb 26;5:3369. doi: 10.1038/ncomms4369.

Delayed bactericidal response of Mycobacterium tuberculosis to bedaquiline involves remodelling of bacterial metabolism.

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Infectious diseases and vaccines therapeutic area, Janssen Research & Development, Johnson & Johnson Pharmaceuticals, Turnhoutseweg 30, 2340 Beerse, Belgium.
Swiss Federal Institute of Technology in Lausanne (EPFL), School of Life Sciences, 1015 Lausanne, Switzerland.
CREATe, Janssen Research & Development, Johnson & Johnson Pharmaceuticals, Turnhoutseweg 30, 2340 Beerse, Belgium.
Department of Biochemistry and Molecular Biology, University of Southern Denmark, Campusvej 55, DK-5230 Odense M, Denmark.
Department of Molecular Cell Biology, AIMMS, VU University Amsterdam, De Boelelaan 1085, 1081 HV Amsterdam, The Netherlands.
Alphalyse A/S, Unsbjergvej 4, DK-5220 Odense SØ, Denmark.


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.

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