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 Yamaguchi, Petros C. Karakousis, Maria Laura Gennaro
Abstract
As our knowledge of host-pathogen interactions grows for many infectious agents, pharmacologically manipulating the host response has emerged as a key approach to control or treat disease-causing infections. This approach may be best suited for infections caused by intracellular pathogens, given the intimate relationship between these pathogens and their host cells. For example, Mycobacterium tuberculosis, the intracellular pathogen causing tuberculosis, can subvert and disable the antimicrobial mechanisms of the host macrophage while adapting to the environmental conditions created by these mechanisms (1, 2). The treatment of active tuberculosis, which typically presents with lung tissue damage, is prolonged and requires multiple drugs, presumably due to the presence of phenotypically diverse M. tuberculosis subpopulations that exhibit antibiotic tolerance and poor penetration of antibiotics into infected tissues (3-5). The prolonged duration of anti-tubercular antibiotic therapy (a minimum of six months for drug-susceptible uncomplicated tuberculosis) poses logistical difficulties for treatment providers and leads to poor patient compliance, particularly in low-resource regions (6). A dramatic consequence of these challenges is the development of antibiotic resistance, which requires treatments that are even more prolonged, less effective, more expensive, and more toxic (7).