Methionine Antagonizes para-Aminosalicylic Acid Activity via Affecting Folate Precursor Biosynthesis in Mycobacterium tuberculosis.
para-Aminosalicylic acid (PAS) is a second-line anti-tubercular drug that is used for the treatment of drug-resistant tuberculosis (TB). PAS efficacy in the treatment of TB is limited by its lower potency against Mycobacterium tuberculosis relative to many other drugs in the TB treatment arsenal. It is known that intrinsic metabolites, such as, para-aminobenzoic acid (PABA) and methionine, antagonize PAS and structurally related anti-folate drugs. While the basis for PABA-mediated antagonism of anti-folates is understood, the mechanism for methionine-based antagonism remains undefined. In the present study, we used both targeted and untargeted approaches to identify factors associated with methionine-mediated antagonism of PAS activity. We found that synthesis of folate precursors as well as a putative amino acid transporter, designated MetM, play crucial roles in this process. Disruption of metM by transposon insertion resulted in a ≥30-fold decrease in uptake of methionine in M. bovis BCG, indicating that metM is the major facilitator of methionine transport. We also discovered that intracellular biotin confers intrinsic PAS resistance in a methionine-independent manner. Collectively, our results demonstrate that methionine-mediated antagonism of anti-folate drugs occurs through sustained production of folate precursors.
['Howe|Michael D|MD|', 'Kordus|Shannon L|SL|', 'Cole|Malcolm S|MS|', 'Bauman|Allison A|AA|', 'Aldrich|Courtney C|CC|', 'Baughn|Anthony D|AD|', 'Minato|Yusuke|Y|']
D010129:4-Aminobenzoic Acid D010131:Aminosalicylic Acid D000995:Antitubercular Agents D001426:Bacterial Proteins D001710:Biotin D004336:Drug Antagonism D024881:Drug Resistance, Bacterial D005492:Folic Acid D008715:Methionine D008826:Microbial Sensitivity Tests D009161:Mycobacterium D009169:Mycobacterium tuberculosis
methionine antagonism para-aminosalicylic acid Mycobacterium tuberculosis para-aminobenzoic acid anti-folate drug methionine transport biotin