title: Inhibitors of the Cysteine Synthase CysM with Antibacterial Potency against Dormant Mycobacterium tuberculosis.
abstract: 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.
authors.affiliation: Division of Molecular Structural Biology, Department of Medical Biochemistry & Biophysics, Karolinska Institutet , S-171 77 Stockholm, Sweden.
authors.forename: Katharina
authors.initials: K
authors.lastname: Brunner
authors.affiliation: Division of Molecular Structural Biology, Department of Medical Biochemistry & Biophysics, Karolinska Institutet , S-171 77 Stockholm, Sweden.
authors.forename: Selma
authors.initials: S
authors.lastname: Maric
authors.affiliation: Drug Discovery Research Laboratory, Department of Pharmacy, Birla Institute of Technology & Science-Pilani , Hyderabad Campus, Shameerpet, R.R. District, Hyderabad 500078, Andhra Pradesh India.
authors.forename: Rudraraju Srilakshmi
authors.initials: RS
authors.lastname: Reshma
authors.affiliation: 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.
authors.forename: Helena
authors.initials: H
authors.lastname: Almqvist
authors.affiliation: 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.
authors.forename: Brinton
authors.initials: B
authors.lastname: Seashore-Ludlow
authors.affiliation: 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.
authors.forename: Anna-Lena
authors.initials: AL
authors.lastname: Gustavsson
authors.affiliation: Division of Molecular Structural Biology, Department of Medical Biochemistry & Biophysics, Karolinska Institutet , S-171 77 Stockholm, Sweden.
authors.forename: Ömer
authors.initials: Ö
authors.lastname: Poyraz
authors.affiliation: Drug Discovery Research Laboratory, Department of Pharmacy, Birla Institute of Technology & Science-Pilani , Hyderabad Campus, Shameerpet, R.R. District, Hyderabad 500078, Andhra Pradesh India.
authors.forename: Perumal
authors.initials: P
authors.lastname: Yogeeswari
authors.affiliation: 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.
authors.forename: Thomas
authors.initials: T
authors.lastname: Lundbäck
authors.affiliation: 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.
authors.forename: Michaela
authors.initials: M
authors.lastname: Vallin
authors.affiliation: Drug Discovery Research Laboratory, Department of Pharmacy, Birla Institute of Technology & Science-Pilani , Hyderabad Campus, Shameerpet, R.R. District, Hyderabad 500078, Andhra Pradesh India.
authors.forename: Dharmarajan
authors.initials: D
authors.lastname: Sriram
authors.affiliation: Division of Molecular Structural Biology, Department of Medical Biochemistry & Biophysics, Karolinska Institutet , S-171 77 Stockholm, Sweden.
authors.forename: Robert
authors.initials: R
authors.lastname: Schnell
authors.affiliation: Division of Molecular Structural Biology, Department of Medical Biochemistry & Biophysics, Karolinska Institutet , S-171 77 Stockholm, Sweden.
authors.forename: Gunter
authors.initials: G
authors.lastname: Schneider
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D003547:Cysteine Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D003547:Cysteine Synthase