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

Satish R. Malwal, Ben Mazurek, Jihee Ko, Pujun Xie, Chikako Barnes, Christine Varvitsiotis, Matthew D. Zimmerman, Samir Olatunji, Jaeyong Lee, Min Xie, Jansy Sarathy, Martin Caffrey, Natalie C.J. Strynadka, Véronique Dartois, Thomas Dick, Bom Nae Rin Lee, David G. Russell, Eric Oldfield

Research output: Contribution to journalArticlepeer-review

Abstract

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 IC50of 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.

Original languageEnglish (US)
Pages (from-to)7553-7569
Number of pages17
JournalJournal of Medicinal Chemistry
Volume66
Issue number11
DOIs
StatePublished - Jun 8 2023

ASJC Scopus subject areas

  • Drug Discovery
  • Molecular Medicine

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