Drugs for bad bugs: confronting the challenges of antibacterial discovery

Abstract

Despite the well-recognized medical need for new antibiotics, there has been a marked decrease in antibacterial drug discovery, with many companies leaving the area. In addition to the regulatory requirements and competitive commercial environment, which pose significant barriers to investment, there are scientific hurdles to making novel antibacterials that are underappreciated. Bacterial genome sequencing and analysis has greatly enhanced our understanding of evolution and bacterial physiology. In the mid-1990s, many in the scientific community and pharmaceutical industry believed that this knowledge was going to translate into a new generation of antibacterial drugs that acted by novel mechanisms. GlaxoSmithKline (GSK) embraced this 'genomics' approach to antibacterial discovery, using bioinformatic analysis of genomic information to identify target genes, testing the importance of these genes to bacterial viability by genetic means and finally screening compound collections against the target gene product for inhibitor compounds. GSK scientists validated hundreds of candidate genes and ran more than 70 high-throughput screening (HTS) campaigns between 1995–2001. Blind spots in target validation and an inability to find lead compounds from HTS together with the larger problem of making a single compound that has broad-spectrum activity and is safe at the high serum concentrations needed to cover the least susceptible organisms have left an empty industrial antibacterial portfolio. Eleven years after the first bacterial genome was sequenced, there is still not a single agent in the industrial pipeline that can be construed as being derived from genomic efforts. GSK has found that optimizing novel chemical structures that inhibit highly validated targets for drug-like properties is a more promising, if less trendy, route. Since 2002, our strategy has been to invest heavily in a select number of programmes, with large teams of chemists synthesizing drug-like compounds and with biologists focused on accelerating the critical path pharmacology and microbiological efficacy studies for each new compound synthesized. This approach has produced more novel mechanism antibacterial development candidates at GSK in the past 4 years than in the previous 20. However, high attrition rates in clinical development demand a broader industrial involvement and more aggressive research efforts to assure novel mechanism agents for the future.