Investigation into the Mechanism of Action of the Tuberculosis Drug Candidate SQ109 and Its Metabolites and Analogues in Mycobacteria

J Med Chem. 2023 Jun 8;66(11):7553-7569. doi: 10.1021/acs.jmedchem.3c00398. Epub 2023 May 26.


We tested a series of SQ109 analogues against Mycobacterium tuberculosis and M. smegmatis, in addition to determining their uncoupling activity. We then investigated potential protein targets, involved in quinone and cell wall biosynthesis, using "rescue" experiments. There was little effect of menaquinone on growth inhibition by SQ109, but there were large increases in the IC50 of SQ109 and its analogues (up to 20×) on addition of undecaprenyl phosphate (Up), a homologue of the mycobacterial decaprenyl (C50) diphosphate. Inhibition of an undecaprenyl diphosphate phosphatase, an ortholog of the mycobacterial phosphatase, correlated with cell growth inhibition, and we found that M. smegmatis cell growth inhibition could be well predicted by using uncoupler and Up-rescue results. We also investigated whether SQ109 was metabolized inside Mycobacterium tuberculosis, finding only a single metabolite, previously shown to be inactive. The results are of general interest since they help explain the mechanism of SQ109 in mycobacteria.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antitubercular Agents / metabolism
  • Antitubercular Agents / pharmacology
  • Diphosphates / pharmacology
  • Humans
  • Mycobacterium smegmatis
  • Mycobacterium tuberculosis*
  • Tuberculosis* / drug therapy
  • Tuberculosis* / microbiology


  • Antitubercular Agents
  • Diphosphates
  • N-geranyl-N'-(2-adamantyl)ethane-1,2-diamine