Comparative in vitro activities of TR-1710 and moxifloxacin against Mycobacterium kansasii

Abstract

Background: The currently recommended regimen for treatment of pulmonary M. kansasii infection is isoniazid (INH), rifampin (RIF), and ethambutol (EMB) for 12 – 18 months. RIF is the key agent in this regimen and EMB likely decreases the development of resistance to RIF. It is unclear if INH plays a significant role due to its poor in vitro activity against M. kansasii. Improved therapeutic regimens for this pathogen would be useful. The purpose of the present study was to evaluate the comparative in vitro activities of TR-1710, a new pyrimidoindole DNA gyraseB inhibitor, and moxifloxacin, a GyrA inhibitor, against twenty two isolates of M. kansasii. It is unlikely that cross resistance will be a problem with gyrase inhibitors targeting different enzyme subunits. Methods & Materials: TR-1710 and moxifloxacin were obtained from Cubist Pharmaceuticals (San Diego, CA) and Bayer Pharmaceuticals (West Haven, CT) respectively. These compounds were dissolved in DMSO to a concentration of 1 mg/ml prior to freezing at -200C. They were tested in Middlebrook 7H9 broth, pH6.6 supplemented with 10% Middlebrook albumin-dextrose-catalase enrichment at 2 μg/ml – 0.002 μg/ml in polystyrene 96-well round-bottom microtiter plates. To each well, 50 μl of mycobacterial cell suspension was added to yield an initial concentration of about 1 x 105 CFU/ml (range for various isolates tested was 3.8 x103 – 1.2 x 106CFU/ml). Plates were incubated at 370C in ambient air for 7 - 10 days prior to reading. Results: TR-1710 and moxifloxacin had similar activities against M. kansasii in vitro. The MIC50/MIC90 (μg/ml) of TR-1710 and moxifloxacin were 0.03/0.06 and 0.06/0.50 respectively. Conclusion: Based on TR-1710's promising in vitro activity, it would be interesting to evaluate the comparative activities of TR-1710 and moxifloxacin in a murine model of M. kansasii infection, as the next step in defining the potential of gyrase inhibitors in the treatment of these infections in humans.