Unknown

Dataset Information

0

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


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.

SUBMITTER: Bruiners N 

PROVIDER: S-EPMC7707180 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

altmetric image

Publications

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

Bruiners Natalie N   Dutta Noton K NK   Guerrini Valentina V   Salamon Hugh H   Yamaguchi Ken D KD   Karakousis Petros C PC   Gennaro Maria L ML  

Journal of lipid research 20200826 12


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 ev  ...[more]

Similar Datasets

| S-EPMC6287686 | biostudies-literature
| S-EPMC5938032 | biostudies-literature
| S-EPMC6135569 | biostudies-literature
| S-EPMC8184689 | biostudies-literature
| S-EPMC10547473 | biostudies-literature
| S-EPMC10514517 | biostudies-literature
| S-EPMC7677750 | biostudies-literature
| S-EPMC3427256 | biostudies-literature
| S-EPMC3590255 | biostudies-literature
| S-EPMC11018024 | biostudies-literature