Bactericidal activity of the diarylquinoline TMC207 against Mycobacterium tuberculosis outside and within cells

The bactericidal activities of the diarylquinoline TMC207 in a liquid culture medium started with a bacteriostatic phase lasting about 7 days and then continued with a dose-related bactericidal phase. In comparison, its intra-cellular activity in primary mouse peritoneal macrophages (PM) and in the J774 macrophage-like cell line had little or no static phase so that the bactericidal kill was evident by 5-7 days presumably due to low bacterial ATP levels. Bactericidal activities in the three systems were compared by estimating [1] the rate of bacterial killing (K) during exposure to 0.12-1.0 mu g/ml TMC207 which were similar at, -0.35 in the J774 cells and -0.27 in mouse PM (p = 0.6) with each lower than -0.11 in extracellular cultures (p < 0.001) and [2] the TMC207 concentration at the intersection between the curve relating cfu count to TMC207 concentration and the cfu count at day-0, defined as the static concentration. Static concentrations were 0.22 mu g/ml for extra-cellular cultures, 0.17 mu g/ml for mouse PM and 0.06 mu g/ml for J774 cells, significantly lower than the extra-cellular value (p < 0.001). Thus, the intracellular activity of TMC207 is clearly greater than its extra-cellular activity mainly because the preliminary static phase was a shorter or absent. (C) 2010 Elsevier Ltd. All rights reserved.