MetF-Dependent Methionine Biosynthesis Is Required for Mycobacterium tuberculosis Survival and In Vivo Persistence

Area of Science:

• Microbiology
• Biochemistry
• Drug Discovery

Background:

• Methionine biosynthesis is vital for Mycobacterium tuberculosis (M. tuberculosis) survival.
• The in vivo importance of specific enzymes in this pathway is not fully understood.

Purpose of the Study:

• To investigate the in vivo roles of methionine biosynthesis enzymes MetE and MetF in M. tuberculosis.
• To identify potential metabolic drug targets for tuberculosis treatment.

Main Methods:

• Transposon sequencing was performed on Mycobacterium bovis BCG in methionine-free conditions.
• Gene deletion mutants (ΔmetE and ΔmetF) were created in M. tuberculosis.
• In vitro growth assays and a murine infection model were used for evaluation.

Main Results:

• MetF was identified as a major fitness determinant in M. bovis BCG.
• ΔmetE mutant showed vitamin B12-dependent in vitro growth but normal in vivo growth.
• ΔmetF mutant displayed strict methionine auxotrophy in vitro and failed to survive in a murine infection model.
• Structural modeling indicated MetF is distinct from human homologs.

Conclusions:

• MetF is indispensable for M. tuberculosis survival and persistence in vivo.
• MetE is not essential for M. tuberculosis in vivo survival.
• MetF represents a promising and selective drug target for tuberculosis therapy.