Abstract
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.
Highlights
There is an urgent need for new, potent antituberculosis drugs with novel mechanisms of action that can be included in new regimens to shorten the treatment period for TB
AThe MICs of OPC-167832 against M. tuberculosis complex standard strains were determined by an agar proportion method (CLSI document M24-A2 [35])
We present data to show that a new carbostyril derivative, OPC-167832, is a novel anti-TB drug candidate that can potentially be combined with DMD and other, newer anti-TB agents
Summary
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. 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 These results suggest that OPC-167832 is a novel and potent anti-TB agent, and regimens containing OPC167832 and new or repurposed anti-TB drugs may have the potential to shorten the duration of treatment for TB. As part of our ongoing TB drug discovery efforts, we used phenotypic screening methods to identify and optimize compounds with anti-TB activities from a core carbostyril structure, which has been recognized as having good absorption, distribution, metabolism, excretion, and toxicity profiles and has been used as the backbone of numerous drugs [5] These efforts led to a promising compound, OPC-167832 (Fig. 1), with potent anti-TB activities both in vitro and in vivo. We report here the preclinical data for OPC-167832, including the in vivo efficacy of regimens composed of this compound and other new or repurposed anti-TB drugs
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