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.
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.
This is a preview of subscription content
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
House of Lords Select Committee on Science and Technology Seventh Report. Resistance to Antibiotics and Other Antimicrobial Agents [online], (Stationary Office, London, UK, 1998).
Shlaes, D. M. et al. Antibiotic discovery: state of the state. ASM News 70, 275–281 (2004).
Talbot, G. H. et al. Bad bugs need drugs: an update on the development pipeline from the antibacterial availability task force of the IDSA. Clin. Infect. Dis. 42, 657–668 (2006).
Wenzel, R. P. The antibiotic pipeline — challenges, costs, and values. N. Engl. J. Med. 351, 523–526 (2004).
Infectious Disease Society of America. Bad Bugs, No Drugs [online], (2004). Seminal review by key opinion leaders on the shrinking investment by big pharma in antibacterial discovery, and the growing challenge of resistant pathogens.
Tickell, S. The Antibiotic Innovation Study: Expert Voices on a Critical Need [online], (2005).
Nathan, C. Antibiotics at the cross roads. Nature 431, 899–902 (2004).
Kaplan, W. & Laing, R. Priority Medicines for Europe and the World [online], (World Health Organization, Geneva, 2004).
Brown, J. R. & Warren, P. V. Antibiotic discovery: is it in the genes? Drug Discov. Today 3, 564–566 (1998).
Chan, P. F., Macarron, R., Payne, D. J., Zalacain, M. & Holmes, D. J. Novel antibacterials: a genomics approach to drug discovery. Curr. Drug Targets — Infect. Dis. 2, 109–119 (2002).
Chan, P. F. et al. Characterization of a noval fucose-regulated promoter (PfcsK) suitable for gene essentiality and antibacterial mode of action studies in Streptococcus pneumoniae. J. Bacteriol. 185, 2051–2058 (2003).
Zhang, L. et al. Regulated gene expression in Staphylococcus aureus for identifying conditional lethal phenotypes and antibiotic mode of action. Gene 255, 297–305 (2000).
Yin, D. et al. Identification of Antimicrobial targets using a comprehensive genomic approach. Pharmacogenomics 5, 101–113 (2004).
Zalacain, M. et al. A global approach to identify novel broad-spectrum antibacterial targets among proteins of unknown function. J. Mol. Microbiol. Biotechnol. 6, 109–126 (2003).
Jarvest, R. L., et al. Nanomolar inhibitors of Staphylococcus aureus methionyl tRNA synthetase with potent antibacterial activity against Gram-positive pathogens. J. Med. Chem. 45, 1959–1962 (2002).
Payne, D. J. et al. Discovery of a novel and potent class of FabI directed antibacterial agents. Antimicrob. Agents Chemother. 46, 3118–3124 (2002).
Fan, F. et al. Defining and combating the mechanisms of triclosan resistance in clinical isolates of Staphylococcus aureus. Antimicrob. Agents Chemother. 46, 3343–3347 (2002).
Aubert, K. & Zalacain, M. 3 Peptide deformylase inhibitors. Prog. Med. Chem. 44, 109–143 (2006).
Gentry, D. R. et al. Variable sensitivity to bacterial methionyl-tRNA synthetase inhibitors reveals subpopulations of Streptococcus pneumoniae with two distinct methionyl-tRNA synthetase genes. Antimicrob. Agents Chemother. 47, 1784–1789 (2003). An example illustrating the risk associated with exploitation of non-clinically validated targets for antibacterial discovery.
Du, W. et al. Two active forms of UDP-N-acetylglucosamine enolpyruvyl transferase in Gram-positive bacteria. J. Bacteriol. 182, 4146–4152 (2000).
Heath, R. J. & Rock, C. O. A triclosan-resistant bacterial enzyme. Nature 406, 145 (2000).
Payne, D. J., Gwynn, M. N., Holmes, D. J. & Rosenberg, M. Genomic approaches to antibacterial discovery. Methods Mol. Biol. 266, 231–259 (2004).
Andries, K. et al. A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. Science 307, 223–227 (2005).
Heerding, D. A. et al. New benzylidenethiazolidine-doines as antibacterial agents. Bioorg. Med. Chem. Lett. 13, 3771–3773 (2003).
Chan, P. F. et al. Finding the gems using genomic discovery: antibacterial drug discovery strategies — the successes and the challenges. Drug Discov. Today: Ther. Strategies 1, 519–527 (2004)
Pace, N. R. A molecular view of microbial diversity and the biosphere. Science 276, 734 (1997).
Wong, K. K. et al. Engineering a cell-free murein biosynthetic pathway: combinatorial enzymology in drug discovery. J. Am. Chem. Soc. 120, 13527–13528 (1998).
DeVito, J. A. et al. An array of target-specific screening strains for antibacterials discovery. Nature Biotechnol. 20, 478–483 (2002).
Wong, K. K. & Pompliano, D. L. in Resolving the Antibiotic Paradox: Progress in Understanding Drug Resistance and Development of New Antibiotics (eds Rosen, B. P. & Mobashery, S.) (Plenum, New York, 1999)
Feher, M. & Schmidt, J. M. Property distributions: differences between drugs, natural products, and molecules from combinatorial chemistry. J. Chem. Inf. Comput. Sci. 43, 218–227 (2003).
Lipinski, C. A., Lombardo, F., Dominy, B. W. & Feeney, P. J. Experimental and computional approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev. 23, 3–25 (1997).
Walsh, C. T. Combinatorial biosynthesis of antibiotics: challenges and opportunities. Chembiochem 3, 125–134 (2002)
Throup, J. P. et al. A genomic analysis of two-component signal transduction in Streptococcus pneumoniae. Mol. Microbiol. 35, 566–576 (2000).
Ji. Y. et al. Identification of critical staphylococcal genes using conditional phenotypes generated by antisense RNA. Science 293, 2266–2269 (2001)
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.
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.
- 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.
Freshwater protozoa of the genus Paramecium with an oral groove for feeding.
About this article
Cite this article
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
Transposon insertional mutagenesis of diverse yeast strains suggests coordinated gene essentiality polymorphisms
Nature Communications (2022)
Nature Communications (2022)
Discovery of novel DprE1 inhibitors via computational bioactivity fingerprints and structure-based virtual screening
Acta Pharmacologica Sinica (2022)
Nature Reviews Microbiology (2022)
Scientific Reports (2022)