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Drugs for bad bugs: confronting the challenges of antibacterial discovery

Key Points

  • 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.

Abstract

The sequencing of the first complete bacterial genome in 1995 heralded a new era of hope for antibacterial drug discoverers, who now had the tools to search entire genomes for new antibacterial targets. Several companies, including GlaxoSmithKline, moved back into the antibacterials area and embraced a genomics-derived, target-based approach to screen for new classes of drugs with novel modes of action. Here, we share our experience of evaluating more than 300 genes and 70 high-throughput screening campaigns over a period of 7 years, and look at what we learned and how that has influenced GlaxoSmithKline's antibacterials strategy going forward.

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Figure 1: Estimated success metrics and timelines for the development of a systemic broad-spectrum antibacterial.
Figure 2: Method for testing gene essentiality.
Figure 3: Results of gene essentiality testing in Streptococcus pneumoniae.
Figure 4: The chemical diversity of antibacterials is different to other drugs.

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Acknowledgements

We thank the numerous scientists from all parts of GSK who have contributed to the data discussed in this review and thank C. Edge (GSK, Molecular Discovery Research) for figure 4.

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Correspondence to David L. Pompliano.

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Competing interests

D.J.P, M.N.G., D.J.H. and D.L.P. are employees of GlaxoSmithKline, which is involved in the discovery and commercialization of therapeutics for the treatment of antibacterial infections.

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FURTHER INFORMATION

Centers for Medicines Research

Drugs @ FDA

Glossary

Antibacterial development candidate

A compound that achieves target antibacterial activity in vitro (MIC90s) and in vivo (infection models), shows a viable therapeutic window based on rodent toxicity, and has physical and pharmaceutical properties suitable for preclinical GLP toxicology studies.

Paramecia

Freshwater protozoa of the genus Paramecium with an oral groove for feeding.

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Payne, D., Gwynn, M., Holmes, D. et al. Drugs for bad bugs: confronting the challenges of antibacterial discovery. Nat Rev Drug Discov 6, 29–40 (2007). https://doi.org/10.1038/nrd2201

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