title: Bactericidal activity of the diarylquinoline TMC207 against Mycobacterium tuberculosis outside and within cells.
abstract: 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 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.
authors: St George's University of London, UK.
authors: Jasvir
authors: J
authors: Dhillon
authors: Koen
authors: K
authors: Andries
authors: Patrick P J
authors: PP
authors: Phillips
authors: Denis A
authors: DA
authors: Mitchison
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000995:Antitubercular Agents / Q000494:pharmacology*; D002460:Cell Line; D064687:Diarylquinolines; D017737:Macrophages, Peritoneal / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D011804:Quinolines / Q000494:pharmacology*; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy* / Q000382:microbiology
chemical_list: D000900:Anti-Bacterial Agents; D000995:Antitubercular Agents; D064687:Diarylquinolines; D011804:Quinolines; C493870:bedaquiline