Identifying a novel mechanism of L-leucine uptake in Mycobacterium tuberculosis using a chemical genomic approach.

Semapimod inhibits L-leucine uptake in Mycobacterium tuberculosis, reducing bacterial load in infected mice despite no in vitro efficacy.

• Why it matters: Understanding amino acid transport mechanisms in Mtb is crucial because they support bacterial growth and survival within hosts, yet these pathways are poorly characterized.
• What they did: Researchers screened an FDA-approved drug library against a leucine-auxotrophic Mtb strain, identifying semapimod as a selective inhibitor that disrupts L-leucine uptake by targeting a cell-wall lipid biosynthesis protein.
• The result: This discovery uncovers a novel leucine transport mechanism in Mtb, highlighting its role in intracellular persistence and suggesting new therapeutic targets for tuberculosis treatment.