Antibacterial drug discovery in the resistance era

Abstract

The looming antibiotic-resistance crisis has penetrated the consciousness of clinicians, researchers, policymakers, politicians and the public at large. The evolution and widespread distribution of antibiotic-resistance elements in bacterial pathogens has made diseases that were once easily treatable deadly again. Unfortunately, accompanying the rise in global resistance is a failure in antibacterial drug discovery. Lessons from the history of antibiotic discovery and fresh understanding of antibiotic action and the cell biology of microorganisms have the potential to deliver twenty-first century medicines that are able to control infection in the resistance era. Organized with respect to the prevalent models of each era, this timeline highlights the history and future of antibiotic drug discovery. The golden era was initiated by the discovery of sulfonamide and penicillin and is typified by the methods of Selman Waksman and his contemporaries, who used whole-cell screening of natural product extracts to find new antibiotic scaffolds. In subsequent years, termed the medicinal-chemistry era, these scaffolds were modified chemically. Emphasis in the resistance era has fallen on target-based drug discovery to find broad-spectrum agents — a model that has failed to provide new antibiotics. In the future, a focus on innovative methods and unconventional targets should help to create narrow-spectrum agents and associated diagnostics. A Venn diagram to show a relative profile of target genes for a hypothetical bacterial pathogen. Three potential target sets can be imagined. Each has a relative innovation risk within the context of modern industrial drug discovery, which is indicated on the graph. By far the biggest set can be found in the genes that are needed for infection in a relevant animal model, but much validation remains to be done for these targets. The set that is required for growth on nutrient-limited media is well charted. However, not all of the genes in this set will be required for in vivo infection. Antibiotic drug discovery under nutrient-rich conditions has been the convention for many years, and the corresponding set of target genes is the smallest. The network map illustrates the dense connectivity of enhancing interactions that affect the activity of 39 antibiotics that target the bacterium Escherichia coli. Grey balls represent genes and coloured ones are for antibiotics of various mechanistic classes. Interactions are denoted by connecting lines. The map is derived from data in ref. 35 and was prepared with the BioLayout Express3D network visualization and analysis tool83. Already a subscriber? Log in now or Register for online access.