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The anti-tubercular activity of simvastatin is mediated by cholesterol-dependent regulation of autophagy via the AMPK-mTORC1-TFEB axis

Natalie Bruiners, Noton K. Dutta, Valentina Guerrini, Hugh Salamon, Ken D. Yamaguchi, Petros C. Karakousis, Maria L. Gennaro
doi: https://doi.org/10.1101/2020.03.04.977579
Natalie Bruiners
1Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, NJ
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Noton K. Dutta
2Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD
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Valentina Guerrini
1Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, NJ
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Hugh Salamon
3Knowledge Synthesis Inc., Berkeley, CA
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Ken D. Yamaguchi
3Knowledge Synthesis Inc., Berkeley, CA
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Petros C. Karakousis
2Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD
4Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD
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Maria L. Gennaro
1Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, NJ
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  • For correspondence: marila.gennaro@rutgers.edu
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ABSTRACT

Statins, which inhibit both cholesterol biosynthesis and protein prenylation branches of the mevalonate pathway, increase anti-tubercular antibiotic efficacy in animal models. We investigated the mechanism of anti-tubercular action of simvastatin in Mycobacterium tuberculosis-infected human monocytic cells. We found that the anti-tubercular activity of statins was phenocopied by cholesterol-branch but not prenylation-branch inhibitors. Moreover, statin treatment blocked activation of mechanistic target of rapamycin complex 1 (mTORC1), activated AMP-activated protein kinase (AMPK) through increased intracellular AMP:ATP ratios, and favored nuclear translocation of transcription factor EB (TFEB). These mechanisms all induce autophagy, which is anti-mycobacterial. The biological effects of simvastatin on the AMPK-mTORC1-TFEB-autophagy axis were reversed by adding exogenous cholesterol to the cells. Overall, our data demonstrate that the anti-tubercular activity of simvastatin requires inhibiting cholesterol biosynthesis, reveal novel links between cholesterol homeostasis, AMPK-mTORC1-TFEB axis, and intracellular infection control, and uncover new anti-tubercular therapy targets.

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Posted March 05, 2020.
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The anti-tubercular activity of simvastatin is mediated by cholesterol-dependent regulation of autophagy via the AMPK-mTORC1-TFEB axis
Natalie Bruiners, Noton K. Dutta, Valentina Guerrini, Hugh Salamon, Ken D. Yamaguchi, Petros C. Karakousis, Maria L. Gennaro
bioRxiv 2020.03.04.977579; doi: https://doi.org/10.1101/2020.03.04.977579
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The anti-tubercular activity of simvastatin is mediated by cholesterol-dependent regulation of autophagy via the AMPK-mTORC1-TFEB axis
Natalie Bruiners, Noton K. Dutta, Valentina Guerrini, Hugh Salamon, Ken D. Yamaguchi, Petros C. Karakousis, Maria L. Gennaro
bioRxiv 2020.03.04.977579; doi: https://doi.org/10.1101/2020.03.04.977579

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