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

Anil Koul (), Luc Vranckx, Neeraj Dhar, Hinrich W.H. Göhlmann, Emre Özdemir, Jean-Marc Neefs, Melanie Schulz, Ping Lu, Ejvind Mørtz, John D. McKinney, Koen Andries and Dirk Bald
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Anil Koul: Infectious diseases and vaccines therapeutic area, Janssen Research & Development, Johnson & Johnson Pharmaceuticals
Luc Vranckx: Infectious diseases and vaccines therapeutic area, Janssen Research & Development, Johnson & Johnson Pharmaceuticals
Neeraj Dhar: Swiss Federal Institute of Technology in Lausanne (EPFL), School of Life Sciences
Hinrich W.H. Göhlmann: CREATe, Janssen Research & Development, Johnson & Johnson Pharmaceuticals
Emre Özdemir: Swiss Federal Institute of Technology in Lausanne (EPFL), School of Life Sciences
Jean-Marc Neefs: CREATe, Janssen Research & Development, Johnson & Johnson Pharmaceuticals
Melanie Schulz: University of Southern Denmark
Ping Lu: AIMMS, VU University Amsterdam
Ejvind Mørtz: Alphalyse A/S, Unsbjergvej 4, DK-5220 Odense SØ, Denmark
John D. McKinney: Swiss Federal Institute of Technology in Lausanne (EPFL), School of Life Sciences
Koen Andries: Infectious diseases and vaccines therapeutic area, Janssen Research & Development, Johnson & Johnson Pharmaceuticals
Dirk Bald: AIMMS, VU University Amsterdam

Nature Communications, 2014, vol. 5, issue 1, 1-10

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms4369

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