title: In vitro and in vivo activities of the nitroimidazole TBA-354 against Mycobacterium tuberculosis.
abstract: Nitroimidazoles are a promising new class of antitubercular agents. The nitroimidazo-oxazole delamanid (OPC-67683, Deltyba) is in phase III trials for the treatment of multidrug-resistant tuberculosis, while the nitroimidazo-oxazine PA-824 is entering phase III for drug-sensitive and drug-resistant tuberculosis. TBA-354 (SN31354[(S)-2-nitro-6-((6-(4-trifluoromethoxy)phenyl)pyridine-3-yl)methoxy)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine]) is a pyridine-containing biaryl compound with exceptional efficacy against chronic murine tuberculosis and favorable bioavailability in preliminary rodent studies. It was selected as a potential next-generation antituberculosis nitroimidazole following an extensive medicinal chemistry effort. Here, we further evaluate the pharmacokinetic properties and activity of TBA-354 against Mycobacterium tuberculosis. TBA-354 is narrow spectrum and bactericidal in vitro against replicating and nonreplicating Mycobacterium tuberculosis, with potency similar to that of delamanid and greater than that of PA-824. The addition of serum protein or albumin does not significantly alter this activity. TBA-354 maintains activity against Mycobacterium tuberculosis H37Rv isogenic monoresistant strains and clinical drug-sensitive and drug-resistant isolates. Spontaneous resistant mutants appear at a frequency of 3 × 10(-7). In vitro studies and in vivo studies in mice confirm that TBA-354 has high bioavailability and a long elimination half-life. In vitro studies suggest a low risk of drug-drug interactions. Low-dose aerosol infection models of acute and chronic murine tuberculosis reveal time- and dose-dependent in vivo bactericidal activity that is at least as potent as that of delamanid and more potent than that of PA-824. Its superior potency and pharmacokinetic profile that predicts suitability for once-daily oral dosing suggest that TBA-354 be studied further for its potential as a next-generation nitroimidazole.
authors.affiliation: Global Alliance for TB Drug Development, New York, New York, USA anna.upton@tballiance.org.
authors.forename: A M
authors.initials: AM
authors.lastname: Upton
authors.affiliation: Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, USA.
authors.forename: S
authors.initials: S
authors.lastname: Cho
authors.affiliation: Global Alliance for TB Drug Development, New York, New York, USA.
authors.forename: T J
authors.initials: TJ
authors.lastname: Yang
authors.affiliation: Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, People's Republic of China.
authors.forename: Y
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, People's Republic of China.
authors.forename: B
authors.initials: B
authors.lastname: Wang
authors.affiliation: Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, People's Republic of China.
authors.forename: J
authors.initials: J
authors.lastname: Xu
authors.affiliation: Global Alliance for TB Drug Development, New York, New York, USA.
authors.forename: K
authors.initials: K
authors.lastname: Mdluli
authors.affiliation: Global Alliance for TB Drug Development, New York, New York, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Ma
authors.affiliation: Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, USA.
authors.forename: S G
authors.initials: SG
authors.lastname: Franzblau
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004347:Drug Interactions; D024881:Drug Resistance, Bacterial / Q000235:genetics; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D009593:Nitroimidazoles / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010078:Oxazines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010080:Oxazoles / Q000627:therapeutic use; D014376:Tuberculosis / Q000188:drug therapy*
chemical_list: D000995:Antitubercular Agents; D009593:Nitroimidazoles; C516022:OPC-67683; D010078:Oxazines; D010080:Oxazoles; C000600813:TBA-354; C410767:pretomanid