2. Academic Validation
  3. Integrated Target-Based and Phenotypic Screening Approaches for the Identification of Anti-Tubercular Agents That Bind to the Mycobacterial Adenylating Enzyme MbtA

Integrated Target-Based and Phenotypic Screening Approaches for the Identification of Anti-Tubercular Agents That Bind to the Mycobacterial Adenylating Enzyme MbtA

  • ChemMedChem. 2019 Oct 4;14(19):1735-1741. doi: 10.1002/cmdc.201900217.
Lindsay Ferguson 1,  Geoff Wells 2,  Sanjib Bhakta 3,  James Johnson 4,  Junitta Guzman 4,  Tanya Parish 4,  Robin A Prentice 5 6,  Federico Brucoli 7
Affiliations

Affiliations

  • 1 School of Science, University of the West of Scotland, Paisley, PA1 2BE, UK.
  • 2 UCL School of Pharmacy, University College London, 29/39 Brunswick Square, London, WC1N 1AX, UK.
  • 3 Department of Biological Sciences, Institute of Structural and Molecular Biology, Birkbeck, University of London, London, WC1E 7HX, UK.
  • 4 TB Discovery Research, Infectious Disease Research Institute, 1616 Eastlake Avenue East, Seattle, WA, 98102, USA.
  • 5 Seattle Structural Genomics Center for Infectious Disease, Seattle, WA, USA.
  • 6 Center for Global Infectious Disease Research, Seattle Children's Research Institute, 307 Westlake Avenue North, Suite 500, Seattle, WA, USA.
  • 7 Leicester School of Pharmacy, De Montfort University, Leicester, LE1 9BH, UK.
PMID: 31454170 DOI: 10.1002/cmdc.201900217
Abstract

Iron is essential for the pathogenicity and virulence of Mycobacterium tuberculosis, which synthesises salicyl-capped siderophores (mycobactins) to acquire this element from the host. MbtA is the adenylating enzyme that catalyses the initial reaction of mycobactin biosynthesis and is solely expressed by mycobacteria. A 3200-member library comprised of lead-like, structurally diverse compounds was screened against M. tuberculosis for whole-cell inhibitory activity. A set of 846 compounds that inhibited the tubercle bacilli growth were then tested for their ability to bind to MbtA using a fluorescence-based thermal shift assay and NMR-based Water-LOGSY and saturation transfer difference (STD) experiments. We identified an attractive hit molecule, 5-hydroxyindol-3-ethylamino-(2-nitro-4-trifluoromethyl)benzene (5), that bound with high affinity to MbtA and produced a MIC90 value of 13 μm. The ligand was docked into the MbtA crystal structure and displayed an excellent fit within the MbtA active pocket, adopting a binding mode different from that of the established MbtA inhibitor Sal-AMS.

Keywords

NMR spectroscopy; compound screening; iron homeostasis; mycobactins; siderophores; tuberculosis.

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