The antibiotic bedaquiline activates host macrophage innate immune resistance to bacterial infection
Alexandre Giraud-Gatineau,
Juan Manuel Coya,
Alexandra Maure,
Anne Biton,
Michael Thomson,
Elliott M Bernard,
Jade Marrec,
Maximiliano G Gutierrez,
Gérald Larrouy-Maumus,
Roland Brosch,
Brigitte Gicquel,
Ludovic Tailleux
Affiliations
Alexandre Giraud-Gatineau
Unit for Integrated Mycobacterial Pathogenomics, CNRS UMR 3525, Institut Pasteur, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Cellule Pasteur, Paris, France
Juan Manuel Coya
Mycobacterial Genetics Unit, Institut Pasteur, Paris, France
Alexandra Maure
Unit for Integrated Mycobacterial Pathogenomics, CNRS UMR 3525, Institut Pasteur, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Cellule Pasteur, Paris, France
Anne Biton
Bioinformatics and Biostatistics, Department of Computational Biology, USR 3756 CNRS, Institut Pasteur, Paris, France
Michael Thomson
MRC Centre for Molecular Bacteriology and Infection, Department of Life Sciences, Faculty of Natural Sciences, Imperial College London, London, United Kingdom
Elliott M Bernard
Host-Pathogen Interactions in Tuberculosis Laboratory, The Francis Crick Institute, London, United Kingdom
Jade Marrec
Mycobacterial Genetics Unit, Institut Pasteur, Paris, France
Host-Pathogen Interactions in Tuberculosis Laboratory, The Francis Crick Institute, London, United Kingdom
Gérald Larrouy-Maumus
MRC Centre for Molecular Bacteriology and Infection, Department of Life Sciences, Faculty of Natural Sciences, Imperial College London, London, United Kingdom
Roland Brosch
Unit for Integrated Mycobacterial Pathogenomics, CNRS UMR 3525, Institut Pasteur, Paris, France
Brigitte Gicquel
Mycobacterial Genetics Unit, Institut Pasteur, Paris, France; Department of Tuberculosis Control and Prevention, Shenzhen Nanshan Center for Chronic Disease Control, Shenzhen, China
Unit for Integrated Mycobacterial Pathogenomics, CNRS UMR 3525, Institut Pasteur, Paris, France; Mycobacterial Genetics Unit, Institut Pasteur, Paris, France
Antibiotics are widely used in the treatment of bacterial infections. Although known for their microbicidal activity, antibiotics may also interfere with the host’s immune system. Here, we analyzed the effects of bedaquiline (BDQ), an inhibitor of the mycobacterial ATP synthase, on human macrophages. Genome-wide gene expression analysis revealed that BDQ reprogramed cells into potent bactericidal phagocytes. We found that 579 and 1,495 genes were respectively differentially expressed in naive- and M. tuberculosis-infected macrophages incubated with the drug, with an over-representation of lysosome-associated genes. BDQ treatment triggered a variety of antimicrobial defense mechanisms, including phagosome-lysosome fusion, and autophagy. These effects were associated with activation of transcription factor EB, involved in the transcription of lysosomal genes, resulting in enhanced intracellular killing of different bacterial species that were naturally insensitive to BDQ. Thus, BDQ could be used as a host-directed therapy against a wide range of bacterial infections.
