TY - JOUR
T1 - Investigation into the Mechanism of Action of the Tuberculosis Drug Candidate SQ109 and Its Metabolites and Analogues in Mycobacteria
AU - Malwal, Satish R.
AU - Mazurek, Ben
AU - Ko, Jihee
AU - Xie, Pujun
AU - Barnes, Chikako
AU - Varvitsiotis, Christine
AU - Zimmerman, Matthew D.
AU - Olatunji, Samir
AU - Lee, Jaeyong
AU - Xie, Min
AU - Sarathy, Jansy
AU - Caffrey, Martin
AU - Strynadka, Natalie C.J.
AU - Dartois, Véronique
AU - Dick, Thomas
AU - Lee, Bom Nae Rin
AU - Russell, David G.
AU - Oldfield, Eric
N1 - Publisher Copyright:
© 2023 American Chemical Society. All rights reserved.
PY - 2023/6/8
Y1 - 2023/6/8
N2 - 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.
AB - 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.
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U2 - 10.1021/acs.jmedchem.3c00398
DO - 10.1021/acs.jmedchem.3c00398
M3 - Article
C2 - 37235809
AN - SCOPUS:85162193002
SN - 0022-2623
VL - 66
SP - 7553
EP - 7569
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 11
ER -