OPC-167832, a Novel Carbostyril Derivative with Potent Antituberculosis Activity as a DprE1 Inhibitor
Autor: | Motohiro Itotani, Makoto Matsumoto, Izuru Nakamura, Ohba Yoshio, Toshio Shinohara, Yohei Hayashi, Norimitsu Hariguchi, Shunpei Ishikawa, Miki Matsuba, Yoshikazu Kawano, Yoshikazu Haraguchi, Yukitaka Uematsu, Xiuhao Chen, Mamoru Fujiwara, Ryuki Kitamoto, Hiroshi Shimizu, Isao Takemura |
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Rok vydání: | 2020 |
Předmět: |
Tuberculosis
OPC-167832 Antitubercular Agents Quinolones Pharmacology Mycobacterium tuberculosis Mice 03 medical and health sciences chemistry.chemical_compound Moxifloxacin Levofloxacin medicine Animals antituberculosis agent Pharmacology (medical) DprE1 inhibitor 030304 developmental biology 0303 health sciences biology 030306 microbiology business.industry medicine.disease biology.organism_classification Regimen Infectious Diseases carbostyril derivative chemistry Linezolid Hydroxyquinolines Delamanid Bedaquiline business medicine.drug |
Zdroj: | Antimicrobial Agents and Chemotherapy |
ISSN: | 1098-6596 0066-4804 |
Popis: | There is an urgent need for new, potent antituberculosis (anti-TB) drugs with novel mechanisms of action that can be included in new regimens to shorten the treatment period for TB. After screening a library of carbostyrils, we optimized 3,4-dihydrocarbostyril derivatives and identified OPC-167832 as having potent antituberculosis activity. The MICs of the compound for Mycobacterium tuberculosis ranged from 0.00024 to 0.002 μg/ml. It had bactericidal activity against both growing and intracellular bacilli, and the frequency of spontaneous resistance for M. tuberculosis H37Rv was less than 1. There is an urgent need for new, potent antituberculosis (anti-TB) drugs with novel mechanisms of action that can be included in new regimens to shorten the treatment period for TB. After screening a library of carbostyrils, we optimized 3,4-dihydrocarbostyril derivatives and identified OPC-167832 as having potent antituberculosis activity. The MICs of the compound for Mycobacterium tuberculosis ranged from 0.00024 to 0.002 μg/ml. It had bactericidal activity against both growing and intracellular bacilli, and the frequency of spontaneous resistance for M. tuberculosis H37Rv was less than 1.91 × 10−7. It did not show antagonistic effects with other anti-TB agents in an in vitro 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. |
Databáze: | OpenAIRE |
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