Discovery of novel bacterial topoisomerase I inhibitors by use of in silico docking and in vitro assays

Sci Rep. 2018 Jan 23;8(1):1437. doi: 10.1038/s41598-018-19944-4.


Topoisomerases are important targets for antibacterial and anticancer therapies. Bacterial topoisomerase I remains to be exploited for antibiotics that can be used in the clinic. Inhibitors of bacterial topoisomerase I may provide leads for novel antibacterial drugs against pathogens resistant to current antibiotics. TB is the leading infectious cause of death worldwide, and new TB drugs against an alternative target are urgently needed to overcome multi-drug resistance. Mycobacterium tuberculosis topoisomerase I (MtbTopI) has been validated genetically and chemically as a TB drug target. Here we conducted in silico screening targeting an active site pocket of MtbTopI. The top hits were assayed for inhibition of MtbTopI activity. The shared structural motif found in the active hits was utilized in a second round of in silico screening and in vitro assays, yielding selective inhibitors of MtbTopI with IC50s as low as 2 µM. Growth inhibition of Mycobacterium smegmatis by these compounds in combination with an efflux pump inhibitor was diminished by the overexpression of recombinant MtbTopI. This work demonstrates that in silico screening can be utilized to discover new bacterial topoisomerase I inhibitors, and identifies a novel structural motif which could be explored further for finding selective bacterial topoisomerase I inhibitors.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Anti-Bacterial Agents / chemistry*
  • Anti-Bacterial Agents / pharmacology
  • Bacterial Proteins / metabolism
  • Catalytic Domain / drug effects
  • Computer Simulation
  • DNA Topoisomerases, Type I / chemistry*
  • DNA Topoisomerases, Type I / metabolism
  • Drug Discovery
  • Drug Resistance, Bacterial / drug effects
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Molecular Docking Simulation
  • Mycobacterium smegmatis / drug effects
  • Mycobacterium smegmatis / growth & development
  • Mycobacterium tuberculosis / drug effects
  • Mycobacterium tuberculosis / enzymology*
  • Topoisomerase I Inhibitors / chemistry*
  • Topoisomerase I Inhibitors / pharmacology


  • Anti-Bacterial Agents
  • Bacterial Proteins
  • Topoisomerase I Inhibitors
  • DNA Topoisomerases, Type I