Quinolones were examined for rapid lethal activity against Mycobacterium smegmatis in the presence and absence of chloramphenicol, an inhibitor of protein synthesis. C-8 methoxy, C-6 fluorine, and particular C-7 ring substituents enhanced rapid killing. With the surprising exception of moxifloxacin, higher quinolone concentrations were required for lethal activity in the presence of chloramphenicol than in its absence. Moxifloxacin was also unusual in lacking the time lag characteristic of fluoroquinolone lethality. Several fluoroquinolone dimers, which represent quinolones with large C-7 substituents, showed modest bacteriostatic activity. Unlike other quinolones, the dimers failed to display lethal activity. The insensitivity of moxifloxacin to chloramphenicol has not been observed with other bacteria and may therefore reflect unique aspects of mycobacterial gyrase.The fluoroquinolones are lethal, broad-spectrum antibacterial agents that are receiving increasing attention as potential antituberculosis agents. Two new C-8 methoxy derivatives, gatifloxacin and moxifloxacin, exhibit good activity against Mycobacterium tuberculosis, both in vitro (5,12,16) and in a murine model of tuberculosis (1,14,22). Moxifloxacin is now being used clinically (7). However, the lethal activity of the compounds may be reduced by cotreatment with rifampin (12), a first-line antituberculosis drug, and like many other antimycobacterial compounds, fluoroquinolones have marginal activity against nongrowing cells (20,21). The latter feature may be particularly problematic because M. tuberculosis appears to enter a nongrowing, dormant stage shortly after infection (15,17). Thus, understanding how the quinolones rapidly kill bacteria, especially in the absence of growth, is likely to be important.The quinolones reversibly trap gyrase on DNA as complexes in which the DNA is broken (6,18,19). The complexes block DNA replication, thereby explaining the bacteriostatic action of the drugs. After long incubation, the absence of DNA replication leads to cell death through unspecified events. Lethal action can also be seen for short drug treatments if drug concentration is raised to roughly 5 to 10 times the MIC. This rapid lethal action is thought to be due to chromosome fragmentation arising from release of DNA breaks from protein-mediated constraints present in the drug-gyrase-DNA complexes (2). By expressing quinolone concentrations required for rapid death as multiples of bacteriostatic concentrations (fold of MIC), quinolones can be indirectly compared for chromosome fragmentation, independent of effects on processes such as drug uptake, drug efflux, and formation of quinolone-enzyme-DNA complexes.In the present work, we examined Mycobacterium smegmatis for the effect of several quinolone substituents on rapid lethal action. Surprising activities were observed with moxifloxacin and quinolone dimers. Moxifloxacin killed cells equally well in the presence and absence of chloramphenicol, an agent widely known to interfere with quinolone letha...
