2. Academic Validation
  3. Structure Guided Lead Generation toward Nonchiral M. tuberculosis Thymidylate Kinase Inhibitors

Structure Guided Lead Generation toward Nonchiral M. tuberculosis Thymidylate Kinase Inhibitors

  • J Med Chem. 2018 Apr 12;61(7):2753-2775. doi: 10.1021/acs.jmedchem.7b01570.
Lijun Song 1,  Romain Merceron 2 3,  Begoña Gracia 4 5,  Ainhoa Lucía Quintana 4 5,  Martijn D P Risseeuw 1,  Fabian Hulpia 1,  Paul Cos 6,  José A Aínsa 4 5,  Hélène Munier-Lehmann 7,  Savvas N Savvides 2 3,  Serge Van Calenbergh 1
Affiliations

Affiliations

  • 1 Laboratory for Medicinal Chemistry (FFW) , Ghent University , Ottergemsesteenweg 460 , B-9000 Gent , Belgium.
  • 2 VIB Center for Inflammation Research , Zwijnaarde, Ghent 9052 , Belgium.
  • 3 Department of Biochemistry and Microbiology , Ghent University , Ghent 9000 , Belgium.
  • 4 Grupo de Genética de Micobacterias, Departamento de Microbiología, Facultad de Medicina, and BIFI , Universidad de Zaragoza , Zaragoza , Spain.
  • 5 CIBER Enfermedades Respiratorias (CIBERES) , Instituto de Salud Carlos III , 28029 Madrid , Spain.
  • 6 Laboratory for Microbiology, Parasitology and Hygiene (LMPH), Department of Pharmaceutical Sciences , University of Antwerp , Campus Drie Eiken, Universiteitsplein 1 , B-2610 Antwerpen , Belgium.
  • 7 Unit of Chemistry and Biocatalysis, Department of Structural Biology and Chemistry , Institut Pasteur, CNRS UMR3523 , 28 Rue du Dr. Roux , Cedex 15 75724 Paris , France.
PMID: 29510037 DOI: 10.1021/acs.jmedchem.7b01570
Abstract

In recent years, thymidylate kinase (TMPK), an Enzyme indispensable for Bacterial DNA biosynthesis, has been pursued for the development of new Antibacterial agents including against Mycobacterium tuberculosis, the causative agent for the widespread infectious disease tuberculosis (TB). In response to a growing need for more effective anti-TB drugs, we have built upon our previous efforts toward the exploration of novel and potent Mycobacterium tuberculosis TMPK ( MtTMPK) inhibitors, and reported here the design of a novel series of non-nucleoside inhibitors of MtTMPK. The inhibitors display hitherto unexplored interactions in the active site of MtTMPK, offering new insights into structure-activity relationships. To investigate the discrepancy between Enzyme inhibitory activity and the whole-cell activity, experiments with efflux pump inhibitors and efflux pump knockout mutants were performed. The minimum inhibitory concentrations of particular inhibitors increased significantly when determined for the efflux pump mmr knockout mutant, which partly explains the observed dissonance.

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