AUTHOR=Howe Michael D. , Kordus Shannon L. , Cole Malcolm S. , Bauman Allison A. , Aldrich Courtney C. , Baughn Anthony D. , Minato Yusuke 

TITLE=Methionine Antagonizes para-Aminosalicylic Acid Activity via Affecting Folate Precursor Biosynthesis in Mycobacterium tuberculosis

JOURNAL=Frontiers in Cellular and Infection Microbiology

VOLUME=8

YEAR=2018

URL=https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2018.00399

DOI=10.3389/fcimb.2018.00399

ISSN=2235-2988

ABSTRACT=<p><italic>para</italic>-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 <italic>Mycobacterium tuberculosis</italic> relative to many other drugs in the TB treatment arsenal. It is known that intrinsic metabolites, such as, <italic>para</italic>-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 <italic>metM</italic> by transposon insertion resulted in a ≥30-fold decrease in uptake of methionine in <italic>M. bovis</italic> BCG, indicating that <italic>metM</italic> 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.</p>