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Inhibitors of the Cysteine Synthase CysM with Antibacterial Potency against Dormant Mycobacterium tuberculosis.
Brunner, Katharina; Maric, Selma; Reshma, Rudraraju Srilakshmi; Almqvist, Helena; Seashore-Ludlow, Brinton; Gustavsson, Anna-Lena; Poyraz, Ömer; Yogeeswari, Perumal; Lundbäck, Thomas; Vallin, Michaela; Sriram, Dharmarajan; Schnell, Robert; Schneider, Gunter.
Affiliation
  • Brunner K; Division of Molecular Structural Biology, Department of Medical Biochemistry & Biophysics, Karolinska Institutet , S-171 77 Stockholm, Sweden.
  • Maric S; Division of Molecular Structural Biology, Department of Medical Biochemistry & Biophysics, Karolinska Institutet , S-171 77 Stockholm, Sweden.
  • Reshma RS; Drug Discovery Research Laboratory, Department of Pharmacy, Birla Institute of Technology & Science-Pilani , Hyderabad Campus, Shameerpet, R.R. District, Hyderabad 500078, Andhra Pradesh India.
  • Almqvist H; Chemical Biology Consortium Sweden, Science for Life Laboratory, Division of Translational Medicine & Chemical Biology, Department of Medical Biochemistry & Biophysics, Karolinska Institutet , S-171 65 Solna, Sweden.
  • Seashore-Ludlow B; Chemical Biology Consortium Sweden, Science for Life Laboratory, Division of Translational Medicine & Chemical Biology, Department of Medical Biochemistry & Biophysics, Karolinska Institutet , S-171 65 Solna, Sweden.
  • Gustavsson AL; Chemical Biology Consortium Sweden, Science for Life Laboratory, Division of Translational Medicine & Chemical Biology, Department of Medical Biochemistry & Biophysics, Karolinska Institutet , S-171 65 Solna, Sweden.
  • Poyraz Ö; Division of Molecular Structural Biology, Department of Medical Biochemistry & Biophysics, Karolinska Institutet , S-171 77 Stockholm, Sweden.
  • Yogeeswari P; Drug Discovery Research Laboratory, Department of Pharmacy, Birla Institute of Technology & Science-Pilani , Hyderabad Campus, Shameerpet, R.R. District, Hyderabad 500078, Andhra Pradesh India.
  • Lundbäck T; Chemical Biology Consortium Sweden, Science for Life Laboratory, Division of Translational Medicine & Chemical Biology, Department of Medical Biochemistry & Biophysics, Karolinska Institutet , S-171 65 Solna, Sweden.
  • Vallin M; Chemical Biology Consortium Sweden, Science for Life Laboratory, Division of Translational Medicine & Chemical Biology, Department of Medical Biochemistry & Biophysics, Karolinska Institutet , S-171 65 Solna, Sweden.
  • Sriram D; Drug Discovery Research Laboratory, Department of Pharmacy, Birla Institute of Technology & Science-Pilani , Hyderabad Campus, Shameerpet, R.R. District, Hyderabad 500078, Andhra Pradesh India.
  • Schnell R; Division of Molecular Structural Biology, Department of Medical Biochemistry & Biophysics, Karolinska Institutet , S-171 77 Stockholm, Sweden.
  • Schneider G; Division of Molecular Structural Biology, Department of Medical Biochemistry & Biophysics, Karolinska Institutet , S-171 77 Stockholm, Sweden.
J Med Chem ; 59(14): 6848-59, 2016 07 28.
Article in En | MEDLINE | ID: mdl-27379713
Cysteine is an important amino acid in the redox defense of Mycobacterium tuberculosis, primarily as a building block of mycothiol. Genetic studies have implicated de novo cysteine biosynthesis in pathogen survival in infected macrophages, in particular for persistent M. tuberculosis. Here, we report on the identification and characterization of potent inhibitors of CysM, a critical enzyme in cysteine biosynthesis during dormancy. A screening campaign of 17 312 compounds identified ligands that bind to the active site with micromolar affinity. These were characterized in terms of their inhibitory potencies and structure-activity relationships through hit expansion guided by three-dimensional structures of enzyme-inhibitor complexes. The top compound binds to CysM with 300 nM affinity and displays selectivity over the mycobacterial homologues CysK1 and CysK2. Notably, two inhibitors show significant potency in a nutrient-starvation model of dormancy of Mycobacterium tuberculosis, with little or no cytotoxicity toward mammalian cells.
Subject(s)

Full text: 1 Collection: 01-internacional Health context: 3_ND Database: MEDLINE Main subject: Cysteine Synthase / Enzyme Inhibitors / Anti-Bacterial Agents / Mycobacterium tuberculosis Limits: Animals / Humans Language: En Journal: J Med Chem Year: 2016 Document type: Article

Full text: 1 Collection: 01-internacional Health context: 3_ND Database: MEDLINE Main subject: Cysteine Synthase / Enzyme Inhibitors / Anti-Bacterial Agents / Mycobacterium tuberculosis Limits: Animals / Humans Language: En Journal: J Med Chem Year: 2016 Document type: Article