A multitarget approach to drug discovery inhibiting Mycobacterium tuberculosis PyrG and PanK

Sci Rep. 2018 Feb 16;8(1):3187. doi: 10.1038/s41598-018-21614-4.


Mycobacterium tuberculosis, the etiological agent of the infectious disease tuberculosis, kills approximately 1.5 million people annually, while the spread of multidrug-resistant strains is of great global concern. Thus, continuous efforts to identify new antitubercular drugs as well as novel targets are crucial. Recently, two prodrugs activated by the monooxygenase EthA, 7947882 and 7904688, which target the CTP synthetase PyrG, were identified and characterized. In this work, microbiological, biochemical, and in silico methodologies were used to demonstrate that both prodrugs possess a second target, the pantothenate kinase PanK. This enzyme is involved in coenzyme A biosynthesis, an essential pathway for M. tuberculosis growth. Moreover, compound 11426026, the active metabolite of 7947882, was demonstrated to directly inhibit PanK, as well. In an independent screen of a compound library against PyrG, two additional inhibitors were also found to be active against PanK. In conclusion, these direct PyrG and PanK inhibitors can be considered as leads for multitarget antitubercular drugs and these two enzymes could be employed as a "double-tool" in order to find additional hit compounds.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antitubercular Agents / chemistry
  • Antitubercular Agents / metabolism
  • Antitubercular Agents / pharmacology
  • Bacterial Proteins / metabolism
  • Carbon-Nitrogen Ligases / drug effects*
  • Computer Simulation
  • Drug Discovery / methods*
  • Humans
  • Models, Molecular
  • Mycobacterium tuberculosis / enzymology
  • Phosphotransferases (Alcohol Group Acceptor) / drug effects*
  • Tuberculosis / drug therapy


  • Antitubercular Agents
  • Bacterial Proteins
  • Phosphotransferases (Alcohol Group Acceptor)
  • pantothenate kinase
  • Carbon-Nitrogen Ligases
  • CTP synthetase