Translocase I (encoded by mraY) is an essential enzyme involved in the biosynthesis of peptidoglycans, which makes it an attractive target due to its unique presence in bacteria. Caprazamycin (Fig. 26; 18a-g) and capuramycin (Fig. 27; 19a) inhibit Translocase I with an IC50 of 18 nM and 90 nM, respectively . The lead compounds of the series are SQ-641 (Fig. 27; 19b), which has an MIC of 0.67-1.35 mM against drug-susceptible MTb and 0.081-2.71 |M against MDR-TB , and CPZEN-45 (Fig. 27; 19e), which has an MIC of 2.26 and 9.07 |M against drug-susceptible and MDR-TB, respectively.
SQ-641 shows promising efficacy in the murine model of TB infection and exhibits strong synergistic effects with EMB, STR, and SQ-109 (see Sect. 2.5) . CPZEN-45 also exhibits no significant toxicity and a novel mechanism of action making these nucleoside compounds attractive candidates for TB drug development.
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