Potentiation of rifampin activity in a mouse model of tuberculosis by activation of host transcription factor EB


Autoři: Ruslana Bryk aff001;  Shashirekha Mundhra aff001;  Xiuju Jiang aff001;  Madeleine Wood aff001;  Daniel Pfau aff001;  Elaina Weber aff001;  Suna Park aff001;  Li Zhang aff001;  Colin Wilson aff003;  Renier Van der Westhuyzen aff003;  Leslie Street aff003;  Kelly Chibale aff003;  Matthew Zimmerman aff005;  Véronique Dartois aff005;  Nunzia Pastore aff006;  Andrea Ballabio aff006;  Natalie Hawryluk aff010;  Stacie Canan aff010;  Vikram Khetani aff011;  Joseph Camardo aff011;  Carl Nathan aff001
Působiště autorů: Department of Microbiology and Immunology, Weill Cornell Medicine, New York, New York, United States of America aff001;  Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, New York, New York, United States of America aff002;  Drug Discovery and Development Centre, H3D, University of Cape Town, Rondebosch, South Africa aff003;  South African Medical Research Council Drug Discovery and Development Research Unit, Department of Chemistry and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch, South Africa aff004;  Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, New Jersey, United States of America aff005;  Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America aff006;  Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy aff007;  Medical Genetics, Department of Medical and Translational Sciences, Federico II University, Naples, Italy aff008;  Ian and Dan Duncan Neurological Research Institute, Texas Children Hospital, Houston, Texas, United States of America aff009;  Celgene Global Health, San Diego, California, United States of America aff010;  Celgene Global Health, Summit, New Jersey, United States of America aff011
Vyšlo v časopise: Potentiation of rifampin activity in a mouse model of tuberculosis by activation of host transcription factor EB. PLoS Pathog 16(6): e32767. doi:10.1371/journal.ppat.1008567
Kategorie: Research Article
doi: 10.1371/journal.ppat.1008567

Souhrn

Efforts at host-directed therapy of tuberculosis have produced little control of the disease in experimental animals to date. This is not surprising, given that few specific host targets have been validated, and reciprocally, many of the compounds tested potentially impact multiple targets with both beneficial and detrimental consequences. This puts a premium on identifying appropriate molecular targets and subjecting them to more selective modulation. We discovered an aminopyrimidine small molecule, 2062, that had no direct antimycobacterial activity, but synergized with rifampin to reduce bacterial burden in Mtb infected macrophages and mice and also dampened lung immunopathology. We used 2062 and its inactive congeners as tool compounds to identify host targets. By biochemical, pharmacologic, transcriptomic and genetic approaches, we found that 2062’s beneficial effects on Mtb control and clearance in macrophages and in mice are associated with activation of transcription factor EB via an organellar stress response. 2062-dependent TFEB activation led to improved autophagy, lysosomal acidification and lysosomal degradation, promoting bacterial clearance in macrophages. Deletion of TFEB resulted in the loss of IFNγ-dependent control of Mtb replication in macrophages. 2062 also targeted multiple kinases, such as PIKfyve, VPS34, JAKs and Tyk2, whose inhibition likely limited 2062’s efficacy in vivo. These findings support a search for selective activators of TFEB for HDT of TB.

Klíčová slova:

Autophagic cell death – Inflammation – Kinase inhibitors – Lysosomes – Macrophages – Mycobacterium tuberculosis – Tuberculosis – Tuberculosis drug discovery


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