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

Journal of medicinal chemistry, Volume: 66, Issue: 11
June 8, 2023
Satish R Malwal SR, Ben Mazurek B, Jihee Ko J, Pujun Xie P, Chikako Barnes C, Christine Varvitsiotis C, Matthew D Zimmerman MD, Samir Olatunji S, Jaeyong Lee J, Min Xie M, Jansy Sarathy J, Martin Caffrey M, Natalie C J Strynadka NCJ, Véronique Dartois V, Thomas Dick T, Bom Nae Rin Lee BNR, David G Russell DG, Eric Oldfield E

We tested a series of SQ109 analogues against and , 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 IC of SQ109 and its analogues (up to 20×) on addition of undecaprenyl phosphate (Up), a homologue of the mycobacterial decaprenyl (C) diphosphate. Inhibition of an undecaprenyl diphosphate phosphatase, an ortholog of the mycobacterial phosphatase, correlated with cell growth inhibition, and we found that cell growth inhibition could be well predicted by using uncoupler and Up-rescue results. We also investigated whether SQ109 was metabolized inside , 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.

Courtesy of the U.S. National Library of Medicine