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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.

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Figure 1: Models of antibiotic drug discovery and development.
Figure 2: Target gene sets and innovation risks for a bacterial pathogen.
Figure 3: A chemical–genomic interaction network.

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References

  1. Fleming, A. On the antibacterial action of cultures of a penicillium, with special reference to their use in the isolation of B. influenzae. Br. J. Exp. Pathol. 10, 226–236 (1929).

    CAS  PubMed Central  Google Scholar 

  2. Comroe, J. H. Jr. Pay dirt: the story of streptomycin. Part I. From Waksman to Waksman. Am. Rev. Respir. Dis. 117, 773–781 (1978).

    CAS  PubMed  Google Scholar 

  3. Wright, G. D. The antibiotic resistome: the nexus of chemical and genetic diversity. Nature Rev. Microbiol. 5, 175–186 (2007).

    CAS  Google Scholar 

  4. Perry, J. A., Westman, E. L. & Wright, G. D. The antibiotic resistome: what's new? Curr. Opin. Microbiol. 21, 45–50 (2014).

    CAS  PubMed  Google Scholar 

  5. Forsberg, K. J. et al. Bacterial phylogeny structures soil resistomes across habitats. Nature 509, 612–616 (2014).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  6. Nesme, J. & Simonet, P. The soil resistome: a critical review on antibiotic resistance origins, ecology and dissemination potential in telluric bacteria. Environ. Microbiol. 17, 913–930 (2015).

    PubMed  Google Scholar 

  7. Finley, R. L. et al. The scourge of antibiotic resistance: the important role of the environment. Clin. Infect. Dis. 57, 704–710 (2013).

    PubMed  Google Scholar 

  8. Forsberg, K. J. et al. The shared antibiotic resistome of soil bacteria and human pathogens. Science 337, 1107–1111 (2012).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  9. D'Costa, V. M. et al. Antibiotic resistance is ancient. Nature 477, 457–461 (2011). This paper was the first to provide physical evidence of the ancient resistome, in 30,000-year-old permafrost.

    ADS  CAS  PubMed  Google Scholar 

  10. Andersson, D. I. & Hughes, D. Persistence of antibiotic resistance in bacterial populations. FEMS Microbiol. Rev. 35, 901–911 (2011).

    CAS  PubMed  Google Scholar 

  11. Cox, G. & Wright, G. D. Intrinsic antibiotic resistance: mechanisms, origins, challenges and solutions. Int. J. Med. Microbiol. 303, 287–292 (2013).

    CAS  PubMed  Google Scholar 

  12. Fajardo, A. et al. The neglected intrinsic resistome of bacterial pathogens. PLoS ONE 3, e1619 (2008). An introduction to the concept of the intrinsic resistome, which is a target for antibiotic adjuvants.

    ADS  PubMed  PubMed Central  Google Scholar 

  13. Abraham, E. P. & Chain, E. An enzyme from bacteria able to destroy penicillin. Nature 146, 837 (1940).

    ADS  CAS  Google Scholar 

  14. Davies, J. & Davies, D. Origins and evolution of antibiotic resistance. Microbiol. Mol. Biol. Rev. 74, 417–433 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Fischbach, M. A. & Walsh, C. T. Antibiotics for emerging pathogens. Science 325, 1089–1093 (2009).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  16. Lewis, K. Antibiotics: recover the lost art of drug discovery. Nature 485, 439–440 (2012).

    ADS  CAS  PubMed  Google Scholar 

  17. Cho, H., Uehara, T. & Bernhardt, T. G. β-Lactam antibiotics induce a lethal malfunctioning of the bacterial cell wall synthesis machinery. Cell 159, 1300–1311 (2014). This paper provides evidence for the complexity of antibiotic-induced cell death.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Wilson, D. N. Ribosome-targeting antibiotics and mechanisms of bacterial resistance. Nature Rev. Microbiol. 12, 35–48 (2014).

    CAS  Google Scholar 

  19. Demirci, H. et al. A structural basis for streptomycin-induced misreading of the genetic code. Nature Commun. 4, 1355 (2013).

    ADS  Google Scholar 

  20. Dwyer, D. J., Collins, J. J. & Walker, G. C. Unraveling the physiological complexities of antibiotic lethality. Annu. Rev. Pharmacol. Toxicol. 55, 313–332 (2015).

    CAS  PubMed  Google Scholar 

  21. Macarron, R. et al. Impact of high-throughput screening in biomedical research. Nature Rev. Drug Discov. 10, 188–195 (2011).

    CAS  Google Scholar 

  22. Fleischmann, R. D. et al. Whole-genome random sequencing and assembly of Haemophilus influenzae Rd. Science 269, 496–512 (1995).

    ADS  CAS  PubMed  Google Scholar 

  23. Kobayashi, K. et al. Essential Bacillus subtilis genes. Proc. Natl Acad. Sci. USA 100, 4678–4683 (2003).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  24. Baba, T. et al. Construction of Escherichia coli K-12 in-frame, single-gene knockout mutants: the Keio collection. Mol. Syst. Biol. 2, 2006.0008 (2006).

    PubMed  PubMed Central  Google Scholar 

  25. Forsyth, R. A. et al. A genome-wide strategy for the identification of essential genes in Staphylococcus aureus. Mol. Microbiol. 43, 1387–1400 (2002).

    CAS  PubMed  Google Scholar 

  26. Jacobs, M. A. et al. Comprehensive transposon mutant library of Pseudomonas aeruginosa. Proc. Natl Acad. Sci. USA 100, 14339–14344 (2003).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  27. Jain, P. et al. Specialized transduction designed for precise high-throughput unmarked deletions in Mycobacterium tuberculosis. mBio 5, e01245–14 (2014).

    PubMed  PubMed Central  Google Scholar 

  28. Brown, E. D. & Wright, G. D. New targets and screening approaches in antimicrobial drug discovery. Chem. Rev. 105, 759–774 (2005).

    CAS  PubMed  Google Scholar 

  29. Payne, D. J., Gwynn, M. N., Holmes, D. J. & Pompliano, D. L. Drugs for bad bugs: confronting the challenges of antibacterial discovery. Nature Rev. Drug Discov. 6, 29–40 (2007).

    CAS  Google Scholar 

  30. Silver, L. L. Challenges of antibacterial discovery. Clin. Microbiol. Rev. 24, 71–109 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Tommasi, R., Brown, D. G., Walkup, G. K., Manchester, J. I. & Miller, A. A. ESKAPEing the labyrinth of antibacterial discovery. Nature Rev. Drug Discov. 14, 529–542 (2015). An analysis of the challenges and failures of antibiotic discovery in 'big pharma'.

    CAS  Google Scholar 

  32. Farha, M. A. & Brown, E. D. Unconventional screening approaches for antibiotic discovery. Ann. NY Acad. Sci. 1354, 54–66 (2015).

    ADS  PubMed  Google Scholar 

  33. D'Elia, M. A., Pereira, M. P. & Brown, E. D. Are essential genes really essential? Trends Microbiol. 17, 433–438 (2009).

    CAS  PubMed  Google Scholar 

  34. Joyce, A. R. et al. Experimental and computational assessment of conditionally essential genes in Escherichia coli. J. Bacteriol. 188, 8259–8271 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Nichols, R. J. et al. Phenotypic landscape of a bacterial cell. Cell 144, 143–156 (2011).

    CAS  PubMed  Google Scholar 

  36. Hensel, M., Shea, J. E., Gleeson, C., Jones, M. D. & Dalton, E. Simultaneous identification of bacterial virulence genes by negative selection. Science 269, 400–403 (1995).

    ADS  CAS  PubMed  Google Scholar 

  37. Autret, N. & Charbit, A. Lessons from signature-tagged mutagenesis on the infectious mechanisms of pathogenic bacteria. FEMS Microbiol. Rev. 29, 703–717 (2005).

    CAS  PubMed  Google Scholar 

  38. van Opijnen, T. & Camilli, A. Transposon insertion sequencing: a new tool for systems-level analysis of microorganisms. Nature Rev. Microbiol. 11, 435–442 (2013).

    CAS  Google Scholar 

  39. Turner, K. H., Wessel, A. K., Palmer, G. C., Murray, J. L. & Whiteley, M. Essential genome of Pseudomonas aeruginosa in cystic fibrosis sputum. Proc. Natl Acad. Sci. USA 112, 4110–4115 (2015).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  40. Fahnoe, K. C. et al. Non-traditional antibacterial screening approaches for the identification of novel inhibitors of the glyoxylate shunt in Gram-negative pathogens. PLoS ONE 7, e51732 (2012).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  41. Zlitni, S., Ferruccio, L. F. & Brown, E. D. Metabolic suppression identifies new antibacterial inhibitors under nutrient limitation. Nature Chem. Biol. 9, 796–804 (2013). This paper describes a systematic screening approach for identifying antibacterial antimetabolites.

    CAS  Google Scholar 

  42. Starkey, M. et al. Identification of anti-virulence compounds that disrupt quorum-sensing regulated acute and persistent pathogenicity. PLoS Pathog. 10, e1004321 (2014).

    PubMed  PubMed Central  Google Scholar 

  43. Pethe, K. et al. Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis. Nature Med. 19, 1157–1160 (2013).

    CAS  PubMed  Google Scholar 

  44. Costanzo, M. et al. The genetic landscape of a cell. Science 327, 425–431 (2010).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  45. Ho, Y. et al. Systematic identification of protein complexes in Saccharomyces cerevisiae by mass spectrometry. Nature 415, 180–183 (2002).

    ADS  CAS  PubMed  Google Scholar 

  46. Butland, G. et al. Interaction network containing conserved and essential protein complexes in Escherichia coli. Nature 433, 531–537 (2005).

    ADS  CAS  PubMed  Google Scholar 

  47. Babu, M. et al. Genetic interaction maps in Escherichia coli reveal functional crosstalk among cell envelope biogenesis pathways. PLoS Genet. 7, e1002377 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Gerdes, K., Christensen, S. K. & Løbner-Olesen, A. Prokaryotic toxin–antitoxin stress response loci. Nature Rev. Microbiol. 3, 371–382 (2005).

    CAS  Google Scholar 

  49. D'Elia, M. A. et al. Lesions in teichoic acid biosynthesis in Staphylococcus aureus lead to a lethal gain of function in the otherwise dispensable pathway. J. Bacteriol. 188, 4183–4189 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. D'Elia, M. A. et al. Probing teichoic acid genetics with bioactive molecules reveals new interactions among diverse processes in bacterial cell wall biogenesis. Chem. Biol. 16, 548–556 (2009).

    CAS  PubMed  Google Scholar 

  51. Swoboda, J. G. et al. Discovery of a small molecule that blocks wall teichoic acid biosynthesis in Staphylococcus aureus. ACS Chem. Biol. 4, 875–883 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Wang, H. et al. Discovery of wall teichoic acid inhibitors as potential anti-MRSA β-lactam combination agents. Chem. Biol. 20, 272–284 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Farha, M. A. et al. Inhibition of WTA synthesis blocks the cooperative action of PBPs and sensitizes MRSA to β-lactams. ACS Chem. Biol. 8, 226–233 (2013).

    CAS  PubMed  Google Scholar 

  54. Farha, M. A. et al. Antagonism screen for inhibitors of bacterial cell wall biogenesis uncovers an inhibitor of undecaprenyl diphosphate synthase. Proc. Natl Acad. Sci. USA 112, 11048–11053 (2015).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  55. Liu, A. et al. Antibiotic sensitivity profiles determined with an Escherichia coli gene knockout collection: generating an antibiotic bar code. Antimicrob. Agents Chemother. 54, 1393–1403 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Tan, C. M. et al. Restoring methicillin-resistant Staphylococcus aureus susceptibility to β-lactam antibiotics. Sci. Transl. Med. 4, 126ra35 (2012).

    PubMed  Google Scholar 

  57. Pathania, R. et al. Chemical genomics in Escherichia coli identifies an inhibitor of bacterial lipoprotein targeting. Nature Chem. Biol. 5, 849–856 (2009).

    CAS  Google Scholar 

  58. Brynildsen, M. P., Winkler, J. A., Spina, C. S., Macdonald, I. C. & Collins, J. J. Potentiating antibacterial activity by predictably enhancing endogenous microbial ROS production. Nature Biotechnol. 31, 160–165 (2013).

    CAS  Google Scholar 

  59. Dwyer, D. J. et al. Antibiotics induce redox-related physiological alterations as part of their lethality. Proc. Natl Acad. Sci. USA 111, E2100–E2109 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Taylor, P. L., Rossi, L., De Pascale, G. & Wright, G. D. A forward chemical screen identifies antibiotic adjuvants in Escherichia coli. ACS Chem. Biol. 7, 1547–1555 (2012).

    CAS  PubMed  Google Scholar 

  61. King, A. M. et al. Aspergillomarasmine A overcomes metallo-β-lactamase antibiotic resistance. Nature 510, 503–506 (2014).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  62. Borisy, A. A. et al. Systematic discovery of multicomponent therapeutics. Proc. Natl Acad. Sci. USA 100, 7977–7982 (2003).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  63. Ejim, L. et al. Combinations of antibiotics and nonantibiotic drugs enhance antimicrobial efficacy. Nature Chem. Biol. 7, 348–350 (2011). The first demonstration of a systematic screen for antibiotic adjuvants.

    CAS  Google Scholar 

  64. D'Costa, V. M., McGrann, K. M., Hughes, D. W. & Wright, G. D. Sampling the antibiotic resistome. Science 311, 374–377 (2006).

    ADS  CAS  PubMed  Google Scholar 

  65. Bhullar, K. et al. Antibiotic resistance is prevalent in an isolated cave microbiome. PLoS ONE 7, e34953 (2012).

    ADS  MathSciNet  CAS  PubMed  PubMed Central  Google Scholar 

  66. Bérdy, J. Bioactive microbial metabolites. J. Antibiot. 58, 1–26 (2005).

    Google Scholar 

  67. Baltz, R. H. Marcel Faber Roundtable: is our antibiotic pipeline unproductive because of starvation, constipation or lack of inspiration? J. Ind. Microbiol. Biotechnol. 33, 507–513 (2006).

    CAS  PubMed  Google Scholar 

  68. Lipinski, C. A., Lombardo, F., Dominy, B. W. & Feeney, P. J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev. 46, 3–26 (2001).

    CAS  PubMed  Google Scholar 

  69. O'Shea, R. & Moser, H. E. Physicochemical properties of antibacterial compounds: implications for drug discovery. J. Med. Chem. 51, 2871–2878 (2008).

    CAS  PubMed  Google Scholar 

  70. Kim, J., Kim, H. & Park, S. B. Privileged structures: efficient chemical 'navigators' toward unexplored biologically relevant chemical spaces. J. Am. Chem. Soc. 136, 14629–14638 (2014).

    CAS  PubMed  Google Scholar 

  71. Galloway, W. R., Bender, A., Welch, M. & Spring, D. R. The discovery of antibacterial agents using diversity-oriented synthesis. Chem. Commun. 2009, 2446–2462 (2009).

    Google Scholar 

  72. Rachakonda, V., Alla, M., Kotipalli, S. S. & Ummanni, R. Design, diversity-oriented synthesis and structure activity relationship studies of quinolinyl heterocycles as antimycobacterial agents. Eur. J. Med. Chem. 70, 536–547 (2013).

    CAS  PubMed  Google Scholar 

  73. Han, S., Zaniewski, R. P. & Marr, E. S. Structural basis for effectiveness of siderophore-conjugated monocarbams against clinically relevant strains of Pseudomonas aeruginosa. Proc. Natl Acad. Sci. USA 107, 22002–22007 (2010).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  74. Eisenstein, B. I., Oleson, F. B. & Baltz, R. H. Daptomycin: from the mountain to the clinic, with essential help from Francis Tally, MD. Clin. Infect. Dis. 50 (suppl. 1), S10–S15 (2010).

    CAS  PubMed  Google Scholar 

  75. Gerber, M. & Ackermann, G. OPT-80, a macrocyclic antimicrobial agent for the treatment of Clostridium difficile infections: a review. Expert Opin. Investig. Drugs 17, 547–553 (2008).

    CAS  PubMed  Google Scholar 

  76. Lok, C. Mining the microbial dark matter. Nature 522, 270–273 (2015).

    ADS  CAS  PubMed  Google Scholar 

  77. Wilson, M. C. et al. An environmental bacterial taxon with a large and distinct metabolic repertoire. Nature 506, 58–62 (2014).

    ADS  CAS  PubMed  Google Scholar 

  78. Ling, L. L. et al. A new antibiotic kills pathogens without detectable resistance. Nature 517, 455–459 (2015).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  79. Brown, E. D. Is the GAIN Act a turning point in new antibiotic discovery? Can. J. Microbiol. 59, 153–156 (2013).

    CAS  PubMed  Google Scholar 

  80. Spellberg, B., Bartlett, J., Wunderink, R. & Gilbert, D. N. Novel approaches are needed to develop tomorrow's antibacterial therapies. Am. J. Respir. Crit. Care Med. 191, 135–140 (2015).

    PubMed  PubMed Central  Google Scholar 

  81. Spellberg, B. The future of antibiotics. Crit. Care 18, 228 (2014).

    PubMed  PubMed Central  Google Scholar 

  82. McArthur, A. G. & Wright, G. D. Bioinformatics of antimicrobial resistance in the age of molecular epidemiology. Curr. Opin. Microbiol. 27, 45–50 (2015).

    PubMed  Google Scholar 

  83. Theocharidis, A., van Dongen, S., Enright, A. J. & Freeman, T. C. Network visualization and analysis of gene expression data using BioLayout Express3D. Nature Protoc. 4, 1535–1550 (2009).

    CAS  Google Scholar 

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Acknowledgements

The authors thank M. Farha for stimulating discussion with regards to the manuscript and S. French for creating Fig. 3. This work was supported by Discovery grants from the Natural Sciences and Engineering Research Council of Canada to E.D.B. (RGPIN 04384-2014) and G.D.W. (RGPIN 237480), by salary awards from the Canada Research Chairs Program to both E.D.B. and G.D.W., and by grants from the Canadian Institutes of Health Research to E.D.B. (MOP-81330 and MOP-15496) and G.D.W. (MT-13536).

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Brown, E., Wright, G. Antibacterial drug discovery in the resistance era. Nature 529, 336–343 (2016). https://doi.org/10.1038/nature17042

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