Microbial resistance: Novel screens for a contemporary problem

Historically, natural products have been the source of a large variety of a ntibacterial agents, In the 1980s, no additional useful antibacterial agent s were discovered, leading to the belief that most useful chemotypes from n atural product sources had already been discovered. At this time, advances in biotechnology made it feasible to produce sufficient enzyme to set up ce ll-free screens. Chemical compound libraries and combinatorial synthesis be came the source of chemical diversity for the screens. In spite of these ef forts, very few new antibacterial agents have been discovered in the last d ecade. At Small Molecule Therapeutics, Inc., we have developed phenotype-ba sed screens that take advantage of the natural physiology and biochemistry of the target enzymes. We have developed a screen to identify bacterial DNA gyrase and topoisomerase IV poisons, The "hits" identified in this screen are being characterized further A second screen has also been developed aga inst bacterial topoisomerase 1 in which compounds that cause DNA damage thr ough their interaction with bacterial topoisomerase 1 have been identified. Three of the compounds identified in the screen inhibit DNA relaxation med iated by bacterial topoisomerase I, induce DNA cleavage, are noncytotoxic a t > 10 mu M, and have MICs of 4.0 mu g/mL against Staphylococcus aureus. (C ) 1999 John Wiley & Sons, Inc.