Cyclic Peptide [R4W4] in Improving the Ability of First-Line Antibiotics to InhibitMycobacterium tuberculosisInsidein vitroHuman Granulomas
FRONTIERS IN IMMUNOLOGY
Authors: Hernandez, Joshua; Ashley, David; Cao, Ruoqiong; Abrahem, Rachel; Nguyen, Timothy; To, Kimberly; Yegiazaryan, Aram; David, Ajayi Akinwale; Tiwari, Rakesh Kumar; Venketaraman, Vishwanath
Tuberculosis (TB) is currently one of the leading causes of global mortality. Medical non-compliance due to the length of the treatment and antibiotic side effects has led to the emergence of multidrug-resistant (MDR) strains ofMycobacterium tuberculosis(M. tb) that are difficult to treat. A current therapeutic strategy attempting to circumvent this issue aims to enhance drug delivery to reduce the duration of the antibiotic regimen or dosage of first-line antibiotics. One such agent that may help is cyclic peptide [R4W4], as it has been shown to have antibacterial properties (in combination with tetracycline) against methicillin-resistantStaphylococcus aureus(MRSA) in the past. The objective of this study is to test cyclic peptide [R4W4] both alone and in combination with current first-line antibiotics (either isoniazid or pyrazinamide) to study the effects of inhibition ofM. tbinsidein vitrohuman granulomas. Results from our studies indicate that [R4W4] is efficacious in controllingM. tbinfection in the granulomas and has enhanced inhibitory effects in the presence of first-line antibiotics.
OPC-167832, a Novel Carbostyril Derivative with Potent Antituberculosis Activity as a DprE1 Inhibitor
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
Authors: Hariguchi, Norimitsu; Chen, Xiuhao; Hayashi, Yohei; Kawano, Yoshikazu; Fujiwara, Mamoru; Matsuba, Miki; Shimizu, Hiroshi; Ohba, Yoshio; Nakamura, Izuru; Kitamoto, Ryuki; Shinohara, Toshio; Uematsu, Yukitaka; Ishikawa, Shunpei; Itotani, Motohiro; Haraguchi, Yoshikazu; Takemura, Isao; Matsumoto, Makoto
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.