Rational Approaches to Antibacterial Discovery: Pre-Genomic Directed and Phenotypic Screening

Early antibacterial discovery might be divided into the synthetic and antibiotic traditions. The salvarsan-prontosil strand led to exploration of antimetabolite and other chemotherapeutic approaches, while penicillin’s discovery led to the fruitful exploitation of natural products produced by microorganisms. With the investigation of the mechanisms of action of synthetic and antibiotic agents and the principles of selective toxicity and specifi city of action, the separation becomes less clear. Both modes of discovery yield small molecule inhibitors of essential bacterial functions; both started with empirical discoveries but eventually the search evolved to favor more directed methods of compound selection and design. Over time, the yield of novel antibacterial classes via both synthetic and natural product routes has declined, paralleling the increase in more rational screening methods. Is this a causal relationship or merely a correlation? The history of these directed attempts, especially in the natural products area of antibacterial antibiotic discovery, has been obfuscated due to the conscious effort by pharmaceutical companies to hide their methodology from competitors. Although commercially relevant discoveries were revealed through patent and publication with reasonable speed, it is often only through retrospective reviews written much later by the discoverers – or their informants – that the methods used were uncovered. Often, we do not know when such screens were fi rst used. Luckily, much of the screening methodology used to detect inhibitors of peptidoglycan synthesis has been published over time and forms the bulk of the material in this chapter. In the 1980s through 1990s, when there was actually a good deal of innovative screening Chapter 2 Rational Approaches to Antibacterial Discovery: Pre-Genomic Directed and Phenotypic Screening