Session: Poster Session: New Topoisomerase Inhibitors
Monday, October 27, 2008: 12:00 AM
Room: Hall C
Background: FIN is a novel fluoroquinolone (FQ) belonging to a new 8-cyano subclass. FIN exhibits optimal efficacy at a slightly acidic pH (5.0 - 6.0) under which other FQ show decreased activity. Because of this property, FIN is intended for therapeutic use against bacterial infections associated with an acidic environment. The selectivity of FIN for eukaryotic and bacterial DNA topoisomerase II enzymes was evaluated using quantitative plasmid DNA cleavage assays in vitro. Methods: The ability of FIN, clinafloxacin (CLX), ciprofloxacin (CIP), moxifloxacin (MXF) and enoxacin (ENX) to induce DNA cleavage from human topo IIα, E. coli DNA gyrase and topo IV was quantified and compared based on the cleavage detection limit (CDL), defined as the lowest concentration yielding detectible cleavage product compared with that of the known topo II poison, etoposide (VP16). The CL50 value, defined as the concentration that induces 50% maximum cleavage, was used as an additional endpoint for bacterial enzymes. Results: The activity of FIN against the human enzyme was 250-fold lower than that of VP16 and places it well amongst the other FQ (in terms of fold lowered activity against the human enzyme) viz; CLX (10 - 50), CIP (100 - 250), MXF (500) and ENX (no CDL detectable). FIN, CLX, CIP and MXF exhibited a CDL of 1ng/mL against bacterial DNA gyrase, ENX exhibited lower activity (10ng/mL). FIN, CLX and MXF displayed comparable activity against topo IV (1ng/mL), while CIP (10ng/mL) and ENX (50ng/mL) were less active. CL50 (ng/mL) against gyrase and topo IV respectivly show that FIN (25, 8) was more active against both bacterial targets than CLX (10, 52), CIP (120, 200), MXF (70, 200) and ENX (50, 500). Conclusions: These data indicate that FIN is highly selective for bacterial type II topoisomerases. FIN exhibited superior activity to the comparator FQs in terms of potency against the individual bacterial enzymes and its relative eqipotency against these dual targets.