TY - JOUR T1 - Methionine antagonizes <em>para</em>-aminosalicylic acid activity via affecting folate precursor biosynthesis pathway in <em>Mycobacterium tuberculosis</em> JF - bioRxiv DO - 10.1101/319038 SP - 319038 AU - Michael D. Howe AU - Shannon L. Kordus AU - Malcolm S. Cole AU - Allison A. Bauman AU - Courtney C. Aldrich AU - Anthony D. Baughn AU - Yusuke Minato Y1 - 2018/01/01 UR - http://biorxiv.org/content/early/2018/05/17/319038.abstract N2 - 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 play crucial roles in this process. 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. ER -