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

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 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 u

SUBMITTER: Malwal SR 

PROVIDER: S-EPMC10330530 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature