Quinolines as potential new antibacterial agents

Bacterial resistance to antibiotics is increasing at an alarming rate yet many pharmaceutical companies have discontinued their research efforts in anti-infective discovery. Ample evidence exists that demonstrate that both morbidity and mortality increase when patients are infected with antibiotic resistant strains, particularly when the administration of active agents is delayed. The fluoroquinolone or "quinolone" antibiotics are frequently used to treat patients with severe disease. These agents are broad spectrum, well tolerated antibiotics, however, recent years have seen dramatic increases in resistance to these agents. We have previously shown that "quinoline" agents (anti-malarial drugs)have, in addition to their anti-malarial properties, anti-bacterial effects and we have preliminary evidence suggesting that they may bind at different regions of the topoisomerase target than the "quinolone" antibiotics. Our research aims to exploit this finding and to examine the binding properties of these agents against both bacterial topoisomerases, DNA Gyrase and Topoisomerase IV isolated from both fluoroquinolone susceptible and resistant bacteria. In addition, using mechanistic and structural studies we will determine the molecular mode of action of these drugs against bacterial topoisomerases. This information will then be used to inform structure-based design to fine-tune the quinolines leading to the most efficacious anti-bacterial agents. Our specific aim is to find drugs that will address the increasing problems of fluoroquinolone resistance among common clinical pathogens.