Synergistic Activity of R207910 Combined with Pyrazinamide against Murine Tuberculosis

Abstract

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 (

The protonmotive force is required for maintaining ATP homeostasis and viability of hypoxic, nonreplicating Mycobacterium tuberculosis

“…This compound targets the F 0 F 1 ATP synthase and is the most promising anti-TB drug candidate currently under investigation (15,20,27). R207910 reduces the time of therapy in animal models (15,28) and shows superior sterilization activity compared with standard anti-TB drugs. ¶ In addition, it was shown to be safe when given to humans (15), demonstrating that energy depletion can be specifically achieved in Mtb without affecting mammalian mitochondria.…”

Quinoline and quinolones: promising scaffolds for future antimycobacterial agents

“…Haagsma et al 5 studied the selectivity of TMC207 towards M. tuberculosis ATP synthase over the eukaryotic homologue and found that TMC207 is free from ATP synthesis-related toxicity in mammalian cells. TMC207, when used alone or in combination with existing antimycobacterial drugs, represented a promising future for the treatment of TB 6,7 . In 2012, it was approved by U.S. Food and Drug Administration as a new drug to treat MDR-TB 8 .…”

“…Activity(µg/ml) Activity(µg/ml) 12a mF-Ph H 12b C 6 The further development of 4-(adamantan-1-yl)-2-substituted quinolines led to the development of four series of antimycobacterial compounds, namely: 17 . In this study, 14a, 14b, 14c, 16a and 16b were identified as potent analogs and showed 99% inhibition of M. tuberculosis H 37 Rv at the concentration of 3.125 mg/mL.…”

Development of New Anti-tuberculosis Drug Candidates

“…Of particular interest is the synergy between diarylquinoline and PZA, which seems to be the most effective drug combination for sterilizing infected spleens and lungs (Andries et al 2005). Combinations including TMC207 but not PZA (TMC207-INH-RFP and TMC207-MXF-RFP) were less active than TMC207-PZA-containing regimens administered either alone or with the addition of INH, RFP, or MXF (Ibrahim et al 2007). These results demonstrate a synergistic interaction between TMC207 and PZA.…”