Methionine antagonizes para -aminosalicylic acid activity via affecting folate precursor biosynthesis pathway in Mycobacterium tuberculosis
Methionine antagonizes para -aminosalicylic acid activity via affecting folate precursor biosynthesis pathway in Mycobacterium tuberculosis
Abstract 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.
Howe Michael D.、Bauman Allison A.、Minato Yusuke、Aldrich Courtney C.、Kordus Shannon L.、Cole Malcolm S.、Baughn Anthony D.
Department of Microbiology and Immunology, University of Minnesota Medical SchoolDepartment of Microbiology and Immunology, University of Minnesota Medical SchoolDepartment of Microbiology and Immunology, University of Minnesota Medical SchoolDepartment of Medicinal Chemistry, University of MinnesotaDepartment of Microbiology and Immunology, University of Minnesota Medical SchoolDepartment of Medicinal Chemistry, University of MinnesotaDepartment of Microbiology and Immunology, University of Minnesota Medical School
基础医学药学微生物学
Mycobacterium tuberculosisanti-folate drugpara-aminosalicylic acidmethioninepara-aminobenzoic acidbiotinantagonismmetabolismmethionine transport
Howe Michael D.,Bauman Allison A.,Minato Yusuke,Aldrich Courtney C.,Kordus Shannon L.,Cole Malcolm S.,Baughn Anthony D..Methionine antagonizes para -aminosalicylic acid activity via affecting folate precursor biosynthesis pathway in Mycobacterium tuberculosis[EB/OL].(2025-03-28)[2025-06-27].https://www.biorxiv.org/content/10.1101/319038.点此复制
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