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Methionine Antagonizes para-Aminosalicylic Acid Activity via Affecting Folate Precursor Biosynthesis in Mycobacterium tuberculosis.
Howe, Michael D; Kordus, Shannon L; Cole, Malcolm S; Bauman, Allison A; Aldrich, Courtney C; Baughn, Anthony D; Minato, Yusuke.
Afiliação
  • Howe MD; Department of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, MN, United States.
  • Kordus SL; Department of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, MN, United States.
  • Cole MS; Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN, United States.
  • Bauman AA; Department of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, MN, United States.
  • Aldrich CC; Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN, United States.
  • Baughn AD; Department of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, MN, United States.
  • Minato Y; Department of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, MN, United States.
Article em En | MEDLINE | ID: mdl-30483484
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, 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.
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Texto completo: 1 Coleções: 01-internacional Contexto em Saúde: 2_ODS3 / 3_ND Base de dados: MEDLINE Assunto principal: Ácido Aminossalicílico / Antagonismo de Drogas / Metionina / Mycobacterium tuberculosis / Antituberculosos Tipo de estudo: Prognostic_studies Idioma: En Revista: Front Cell Infect Microbiol Ano de publicação: 2018 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Contexto em Saúde: 2_ODS3 / 3_ND Base de dados: MEDLINE Assunto principal: Ácido Aminossalicílico / Antagonismo de Drogas / Metionina / Mycobacterium tuberculosis / Antituberculosos Tipo de estudo: Prognostic_studies Idioma: En Revista: Front Cell Infect Microbiol Ano de publicação: 2018 Tipo de documento: Article