Recombinant M. Tuberculosis Rv0477 Antigen [His, GST]

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 mu g/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 x 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-beta-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.

Introduction The definition of acute lower respiratory tract infection (LRTI) includes any infection involving the respiratory tract below the level of the larynx. In children, the most common acute LRTIs, and those with the greatest clinical relevance, are community-acquired pneumonia (CAP), bronchiolitis, bronchitis and tuberculosis (TB). The clinical relevance of LRTIs implies that they must be addressed with the most effective therapy. Antibiotics and antivirals play an essential role in this regard. Areas covered In this paper, the most recent advances in the drug treatment of LRTIs in children are discussed. Expert opinion Although LRTIs are extremely common and one of the most important causes of hospitalization and death in children, anti-infective therapy for these diseases remains unsatisfactory. For CAP and BR, the most important problem is the overuse and misuse of antibiotics; for BCL, the lack of drugs with demonstrated efficacy, safety and tolerability; for TB, the poor knowledge on the true efficacy and safety of the new drugs specifically planned to overcome the problem of MDR M. tuberculosis strains. There is still a long way to go for the therapy of pediatric LRTIs to be considered satisfactory.