Repurposing Tamoxifen as Potential Host-Directed Therapeutic for Tuberculosis

Area of Science:

• Infectious Diseases
• Immunology
• Drug Repurposing

Background:

• Tuberculosis (TB) presents a growing global health challenge due to increasing drug resistance in Mycobacterium tuberculosis (Mtb).
• Host-directed therapy (HDT) offers a novel adjunctive strategy to conventional antibiotic treatments for TB.
• Existing therapies face limitations against intracellular Mtb residing within macrophages.

Purpose of the Study:

• To investigate the potential of repurposing the anticancer drug tamoxifen as an HDT agent against Mtb.
• To elucidate the mechanism of action of tamoxifen in combating Mtb infection.
• To evaluate tamoxifen's efficacy against both drug-sensitive and drug-resistant Mtb strains.

Main Methods:

• Utilized a primary human macrophage model infected with Mtb.
• Employed a zebrafish larvae infection model with Mycobacterium marinum to assess in vivo efficacy.
• Conducted RNA sequencing and microscopic colocalization studies to determine tamoxifen's mechanism.

Main Results:

• Tamoxifen demonstrated significant antimycobacterial activity against Mtb in macrophages and in a zebrafish model.
• Tamoxifen's effect was confirmed as host-directed, with no direct antimicrobial activity observed.
• The mechanism involves modulating autophagy and lysosomal pathways, independent of estrogen receptor signaling, enhancing Mtb delivery to lysosomes.

Conclusions:

• Tamoxifen exhibits potent host-directed therapeutic potential for treating tuberculosis.
• Repurposing tamoxifen offers a promising strategy to combat drug-resistant TB infections.
• Modulation of host autophagy and lysosomal pathways is key to tamoxifen's antimycobacterial efficacy.