Biological and Medicinal Chemistry

Discovery of novel drug-like antitubercular hits targeting the MEP pathway enzyme DXPS by strategic application of ligand-based virtual screening

Authors

  • Di Zhu Helmholtz Institute for Pharmaceutical Research Saarland & Saarland University & University of Groningen ,
  • Sandra Johannsen Helmholtz Institute for Pharmaceutical Research Saarland & Saarland University ,
  • Tiziana Masini University of Groningen ,
  • Céline Simonin University of Bern ,
  • Jörg Haupenthal Helmholtz Institute for Pharmaceutical Research Saarland ,
  • Boris Illarionov Hamburg School of Food Science ,
  • Anastasia Andreas Helmholtz Institute for Pharmaceutical Research Saarland & Saarland University ,
  • Mahendra Awale University of Bern ,
  • Robin M. Gierse Helmholtz Institute for Pharmaceutical Research Saarland & University of Groningen & Saarland University ,
  • Tridia van der Laan Department of Mycobacteria, National Institute of Public Health and the Environment ,
  • Ramon van der Vlag University of Groningen ,
  • Rita Nasti University of Groningen ,
  • Mael Poizat Symeres ,
  • Eric Buhler Université Paris Diderot ,
  • Norbert Reiling Research Center Borstel & German Center for Infection Research ,
  • Rolf Müller Helmholtz Institute for Pharmaceutical Research Saarland & Saarland University & Helmholtz International Lab for Anti-infectives ,
  • Markus Fischer Hamburg School of Food Science ,
  • Jean-Louis Reymond University of Bern ,
  • Anna K. H. Hirsch Helmholtz Institute for Pharmaceutical Research Saarland & Saarland University & University of Groningen & Helmholtz International Lab for Anti-infectives

Abstract

In the present manuscript, we describe how we successfully used ligand-based virtual screening (LBVS) to identify two small-molecule, drug-like hit classes with excellent ADMET profiles against the difficult to address microbial enzyme 1-deoxy-D-xylulose-5-phosphate synthase (DXPS). In the fight against antimicrobial resistance (AMR) it has become increasingly important to address novel targets such as DXPS, the first enzyme of the 2C-methyl-D-erythritol-4-phosphate (MEP) pathway, which affords the universal isoprenoid precursors. This pathway is absent in humans but essential for pathogens such as Mycobacterium tuberculosis, making it a rich source of drug targets for the development of novel anti-infectives. Standard computer-aided drug-design tools, frequently applied in other areas of drug development, often fail for targets with large, hydrophilic binding sites such as DXPS. Therefore, we introduce the concept of pseudo-inhibitors, combining the benefits of pseudo-ligands (defining a pharmacophore) and pseudo-receptors (defining anchor points in the binding site), for providing the basis to perform a LBVS against M. tuberculosis DXPS. Starting from a diverse set of reference ligands showing weak inhibition of the orthologue from Deinococcus radiodurans DXPS, we identified three structurally unrelated classes with promising in vitro (against M. tuberculosis DXPS) and whole-cell activity including extensively drug-resistant strains of M. tuberculosis. The hits were validated to be specific inhibitors of DXPS and to have a unique mechanism of inhibition. Furthermore, two of the hits have a balanced profile in terms of metabolic and plasma stability and display a low frequency of resistance development, making them ideal starting points for hit-to-lead optimization of antibiotics with an unprecedented mode of action.

Version notes

Changed affiliation name for Mael Poizat

Content

Thumbnail image of Manuscript_220408.pdf

Supplementary material

Thumbnail image of Supplementary Methods.pdf
Methods
Biological and chemical methods used
Thumbnail image of Supplementary Figures.pdf
Supplementary Figures
Referenced supplementary figures S1-S10
Thumbnail image of Supplementary Tables.pdf
Supplementary Tables
Referenced supplementary tables S1-S5
Thumbnail image of Supplementary Spectra.pdf
Spectra
NMR and MS spectra of active compounds