Structure-Guided Discovery of New Antimicrobial Agents

Abstract

This review provides the current status of structure-guided drug discovery, with examples from antibiotic drug discovery. The article aims to show where and when structural biology has been used “early and often” during the process of antibiotic drug discovery, primarily against novel antibacterial targets. The vast majority of examples are derived from the use of protein crystallization and diffraction information and the high-resolution protein structures that those tools provide. The review provides key examples and a range of methods that have effectively used structural information in various stages of the antibacterial drug discovery process. The starting point for structure-guided drug discovery is most often a high-resolution structure of the target protein. Over the past decade, the publicly funded Protein Structure Initiatives have solved a large number of bacterial protein structures, often from clinically important bacterial species. The public release of these high-resolution structures has enabled structure-guided efforts for antibacterial drug discovery. Many structure-guided methods overcome challenges raised by the limited chemical diversity found in existing chemical diversity libraries.