OPC-167832, a Novel Carbostyril Derivative with Potent Antituberculosis Activity as a DprE1 Inhibitor
Norimitsu Hariguchi, Xiuhao Chen, Yohei Hayashi, Yoshikazu Kawano, Mamoru Fujiwara, Miki Matsuba, Hiroshi Shimizu, Yoshio Ohba, Izuru Nakamura, Ryuki Kitamoto, Toshio Shinohara, Yukitaka Uematsu, Shunpei Ishikawa, Motohiro Itotani, Yoshikazu Haraguchi, Isao Takemura, Makoto Matsumoto
Abstract
checkerboard assay. Whole-genome and targeted sequencing of isolates resistant to OPC-167832 identified decaprenylphosphoryl-β-d-ribose 2'-oxidase (DprE1), an essential enzyme for cell wall biosynthesis, as the target of the compound, and further studies demonstrated inhibition of DprE1 enzymatic activity by OPC-167832. In a mouse model of chronic TB, OPC-167832 showed potent bactericidal activities starting at a dose of 0.625 mg/kg of body weight. Further, it exhibited significant combination effects in 2-drug combinations with delamanid, bedaquiline, or levofloxacin. Finally, 3- or 4-drug regimens comprised of delamanid and OPC-167832 as the core along with bedaquiline, moxifloxacin, or linezolid showed efficacy in reducing the bacterial burden and preventing relapse superior to that of the standard treatment regimen. In summary, these results suggest that OPC-167832 is a novel and potent anti-TB agent, and regimens containing OPC-167832 and new or repurposed anti-TB drugs may have the potential to shorten the duration of treatment for TB.