Synergistic activity of R207910 combined with pyrazinamide against murine tuberculosis

Area of Science:

• Microbiology
• Pharmacology
• Infectious Diseases

Background:

• The diarylquinoline R207910 (TMC207) exhibits bactericidal activity against tuberculosis when combined with standard antitubercular drugs.
• Previous studies highlight the potential of R207910 in tuberculosis treatment regimens.

Purpose of the Study:

• To evaluate the efficacy of R207910 in combination therapies for murine tuberculosis with a high initial bacillary load.
• To assess the synergistic interaction between R207910 and other antitubercular drugs, including pyrazinamide (PZA).

Main Methods:

• Murine model of tuberculosis with a high initial bacillary load (7.2 log(10) CFU).
• Assessment of one-, two-, and three-drug combinations including R207910, isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and moxifloxacin (MXF).
• Evaluation of treatment outcomes based on culture-negative lung homogenates after two months.

Main Results:

• Combinations containing R207910 and PZA (e.g., R207910-PZA, R207910-PZA-INH, R207910-PZA-RIF, R207910-PZA-MXF) achieved culture-negative status in 70-100% of mice.
• Regimens without PZA but including R207910 (e.g., R207910-INH-RIF) were less effective.
• Standard regimens (INH-RIF-PZA) and RIF-MXF-PZA resulted in persistent positive cultures.

Conclusions:

• A synergistic interaction was observed between R207910 and PZA.
• Three-drug combinations featuring R207910 and PZA demonstrate significant potential for shortening tuberculosis treatment duration.
• Further long-term studies are warranted to confirm these findings and assess relapse rates.