title: Contribution of the nitroimidazoles PA-824 and TBA-354 to the activity of novel regimens in murine models of tuberculosis.
abstract: New regimens based on two or more novel agents are sought in order to shorten or simplify the treatment of both drug-susceptible and drug-resistant forms of tuberculosis. PA-824 is a nitroimidazo-oxazine now in phase II trials and has shown significant early bactericidal activity alone and in combination with the newly approved agent bedaquiline or with pyrazinamide with or without moxifloxacin. While the development of PA-824 continues, a potential next-generation derivative, TBA-354, has been discovered to have in vitro potency superior to that of PA-824 and greater metabolic stability than that of the other nitroimidazole derivative in clinical development, delamanid. In the present study, we compared the activities of PA-824 and TBA-354 as monotherapies in murine models of the initial intensive and continuation phases of treatment, as well as in combination with bedaquiline plus pyrazinamide, sutezolid, and/or clofazimine. The monotherapy studies demonstrated that TBA-354 is 5 to 10 times more potent than PA-824, but selected mutants are cross-resistant to PA-824 and delamanid. The combination studies revealed that TBA-354 is 2 to 4 times more potent than PA-824 when combined with bedaquiline, and when administered at a dose equivalent to that of PA-824, TBA-354 demonstrated superior sterilizing efficacy. Perhaps most importantly, the addition of either nitroimidazole significantly improved the sterilizing activities of bedaquiline and sutezolid, with or without pyrazinamide, confirming the value of each agent in this potentially universally active short-course regimen.
authors.affiliation: Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Rokeya
authors.initials: R
authors.lastname: Tasneen
authors.affiliation: Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Kathy
authors.initials: K
authors.lastname: Williams
authors.affiliation: Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Opokua
authors.initials: O
authors.lastname: Amoabeng
authors.affiliation: Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Austin
authors.initials: A
authors.lastname: Minkowski
authors.affiliation: Global Alliance for TB Drug Development, New York, New York, USA.
authors.forename: Khisimuzi E
authors.initials: KE
authors.lastname: Mdluli
authors.affiliation: Global Alliance for TB Drug Development, New York, New York, USA.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Upton
authors.affiliation: Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA enuermb@jhmi.edu.
authors.forename: Eric L
authors.initials: EL
authors.lastname: Nuermberger
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000627:therapeutic use*; D002991:Clofazimine / Q000627:therapeutic use; D064687:Diarylquinolines / Q000627:therapeutic use; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005260:Female; D024841:Fluoroquinolones / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D000077266:Moxifloxacin; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D009593:Nitroimidazoles / Q000627:therapeutic use*; D010078:Oxazines / Q000627:therapeutic use*; D010080:Oxazoles / Q000627:therapeutic use; D011718:Pyrazinamide / Q000627:therapeutic use; D011897:Random Allocation; D014376:Tuberculosis / Q000188:drug therapy*
chemical_list: D000995:Antitubercular Agents; D064687:Diarylquinolines; D024841:Fluoroquinolones; D009593:Nitroimidazoles; C516022:OPC-67683; D010078:Oxazines; D010080:Oxazoles; C000600813:TBA-354; C410767:pretomanid; D011718:Pyrazinamide; C493870:bedaquiline; D002991:Clofazimine; D000077266:Moxifloxacin