TBD Resistence mechanisms and small molecules

The bacterial topoisomerases Gyrase and Topoisomerase IV are well validated targets in antibiotic research and discovery. Fluoroquinolones (eg. Ciprofloxacin) are potent inhibitors of these targets and are an important weapon in the battle against infections. Unfortunately their utility has lately been limited due to emerging resistance. Over the last years several companies have discovered molecules that inhibit topoisomerases by a novel mode of action and are therefore devoid of cross-resistance with clinically used antibiotics including Fluoroquinolones. Especially the Novel Bacterial Topoisomerase Inhibitors (NBTI) such as GSK214944 or NBTI 5436have shown promising properties.[1, 2] We report here the synthesis and characterization of compounds (A) containing a quinolone moiety as well as a pharmacophore contained in NBTI's. Depending on the substitution, these FQ-NBTI hybrids have different modes of action. Very intriguingly is the improved activity on Gram negative bacteria. The presentation will focus on the characterization of the compounds in terms of cellular and enzymatic activities.