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Synergistic Activity of R207910 Combined with Pyrazinamide against Murine Tuberculosis

Laboratoire de Bactériologie, Faculté de Médecine Pitié-Salpêtrière, Université Pierre et Marie Curie Paris 6 and Centre National de Référence de la Résistance des Mycobactéries aux Antituberculeux, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique Hôpitaux de Paris, Paris, France,¹ Antimicrobial Research, Tibotec Pharmaceuticals, Ltd., Johnson & Johnson, Turnhoutseweg 30, 2340 Beerse, Belgium²

Received 20 July 2006/ Returned for modification 8 September 2006/ Accepted 22 November 2006

In previous studies, the diarylquinoline R207910 (also known as TMC207) was demonstrated to have high bactericidal activity when combined with first- or second-line antituberculous drugs. Here we extend the evaluation of R207910 in the curative model of murine tuberculosis by assessing the activities of one-, two-, and three-drug combinations containing R207910 and isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), or moxifloxacin (MXF) in the setting of a high initial bacillary load (7.2 log₁₀ CFU). Two months of treatment with the combinations R207910-PZA, R207910-PZA-INH, R207910-PZA-RIF, or R207910-PZA-MXF resulted in culture-negative lung homogenates in 70 to 100% of the mice, while mice treated with INH-RIF-PZA (the reference regimen) or RIF-MXF-PZA remained culture positive. Combinations including R207910 but not PZA (e.g., R207910-INH-RIF and R207910-MXF-RIF) were less active than R207910-PZA-containing regimens administered either alone or with the addition of INH, RIF, or MXF. These results reveal a synergistic interaction between R207910 and PZA. Three-drug combinations containing these two drugs and INH, RIF, or MXF have the potential to significantly shorten the treatment duration in patients, provided that these results can be confirmed in long-term experiments including periods of relapse.

Published ahead of print on 18 December 2006.

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