The anti-tubercular activity of simvastatin is mediated by cholesterol-driven 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

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

The rise of drug-resistant tuberculosis poses a major risk to public health. Statins, which inhibit both cholesterol biosynthesis and protein prenylation branches of the mevalonate pathway, increase anti-tubercular antibiotic efficacy in animal models. However, the underlying molecular mechanisms are unknown. In this study, we used an in vitro macrophage infection model to investigate simvastatin's anti-tubercular activity by systematically inhibiting each branch of the mevalonate pathway and evaluating the effects of the branch-specific inhibitors on mycobacterial growth. The anti-tubercular activity of simvastatin used at clinically relevant doses specifically targeted the cholesterol biosynthetic branch rather than the prenylation branches of the mevalonate pathway. Using Western blot analysis and AMP/ATP measurements, we found that simvastatin 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. Our data demonstrate that the anti-tubercular activity of simvastatin requires inhibiting cholesterol biosynthesis, reveal novel links between cholesterol homeostasis, the AMPK-mTORC1-TFEB axis, and Mycobacterium tuberculosis infection control, and uncover new anti-tubercular therapy targets.

Original languageEnglish (US)
Pages (from-to)1617-1628
Number of pages12
JournalJournal of lipid research
Volume61
Issue number12
DOIs
StatePublished - Dec 2020

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Endocrinology
  • Cell Biology

Keywords

  • Adenosine 5'-monophosphate-activated protein kinase-mechanistic target of rapamycin complex 1-transcription factor EB axis
  • Immunology
  • Lipids
  • Macrophages/ monocytes
  • Mechanistic target of rapamycin complex 1 regulation
  • Mycobacterium tuberculosis
  • Statins

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