Nuermberger, E.L., Minkowski, A., Mdluli, K.E., Upton, A.M., Tasneen, R., Amoabeng, O., Williams, K.
New regimens based on two or more novel agents are sought to shorten or simplify treatment of both drug-susceptible and drug-resistant forms of tuberculosis. PA-824 is a nitroimidazo-oxazine now in phase 2 trials and has shown significant early bactericidal activity alone and in combination with the newly approved agent bedaquiline or with pyrazinamide ± moxifloxacin. While development of PA-824 continues, a potential next generation derivative TBA-354 has been discovered to have in vitro potency superior to PA-824 and greater metabolic stability than the other nitroimidazole derivative in clinical development, delamanid. In the present study, we compared the activity of PA-824 and TBA-354 as monotherapy in murine models of the initial intensive and continuation phases of treatment and in combination with bedaquiline plus pyrazinamide, sutezolid, and/or clofazimine. The monotherapy studies demonstrated that TBA-354 is 5-10 times more potent than PA-824 but selected mutants cross-resistant to PA-824 and delamanid. The combination studies revealed that TBA-354 was 2-4 times more potent that 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 activity of bedaquiline and sutezolid, with or without pyrazinamide, confirming the value of each agent in this potentially universally active short-course regimen.
Tasneen, R.; Williams, K.; Amoabeng, O.; Minkowski, A.; Mdluli, K.E.; Upton, A.M.; Nuermberger, E.L. Contribution of the Nitroimidazoles PA-824 and TBA-354 to the Activity of Novel Regimens in Murine Models of Tuberculosis. Antimicrobial Agents and Chemotherapy (2015) 59 (1) 129-135. [DOI: 10.1128/AAC.03822-14]