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

SummaryThe 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 μg/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 extra-cellular 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 μg/ml for extra-cellular cultures, 0.17 μg/ml for mouse PM and 0.06 μg/ml for J774 cells, significantly lower than the extra-cellular value (p < 0.001). Thus, the intra-cellular activity of TMC207 is clearly greater than its extra-cellular activity mainly because the preliminary static phase was a shorter or absent.