Novel targets for antibiotics

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Abstract
The rapid and extensive emergence of antibiotic resistant bacteria has resulted in a clear cut need to discover new antibiotics. Because of the many years of extensive screening, it is likely that most of the easy discoveries have been made and, therefore, new targets for antibiotics and new screening strategies for their discovery need to be developed. The approaches described in this overview are divided into several categories that are associated with different probabilities for a successful discovery. Approaches that are more likely to be successful include a continuation of classical discovery tactics including the chemical modification of extant structures, the use of new screens for classical targets (for example, the use of the enzyme DNA gyrase to discover new 4-fluoroquinolones), and the development of novel methods of drug delivery. These approaches, however, are likely to yield small incremental advances. More novel approaches should yield radically new chemical structures, however, the likelihood for a successful discovery will be lower than the classical approaches. The novel approaches include rational drug design, the discovery of new essential targets for antibiotics and using them for the purpose of drug screening, and the intervention in pathways necessary for pathogenesis. A middle of the road approach is to discover new agents that interfere with mechanisms of antibiotic resistance. Implicit in this overview is the need to develop new methods that result in real technologic advances. This may require a complete re-thinking of how antibiotics are discovered including the restricted use of live microbe killing assays as a primary screening tool.