The increasing frequency of nosocomial infections due to multiresistant bacterial pathogens represents a serious health concern and is continuously threatening the therapeutic effectiveness of many antibiotics. This medical need calls for the discovery and development of novel antibiotics and for the improvement of existing compounds. Searching for novel chemical classes of antibiotics requires the identification of validated targets for structure-based design or for their transformation into assays suitable for high throughput screening. The power of bacterial genetics and the genomic revolution have provided us with hundreds of targets, which represent components of a bacterial cell essential for viability, well conserved in the desired range of pathogens, and significantly different from mammalian counterparts. In addition, several technological advances in automation and detection systems enable now the transformation of most validated targets into high throughput screening assays. Are these new targets and assays leading to the discovery of promising novel antibiotics? We will review the recent literature for new chemical classes discovered by high throughput screening, describing also the different assays and screening approaches. In addition, we will provide our own considerations on the need to integrate targets and assays with the type and novelty of the chemical diversity, highlighting the power and limitations of high throughput screening for discovering valuable drug leads.
