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Drug repurposing for antimicrobial discovery

Abstract

Antimicrobial resistance continues to be a public threat on a global scale. The ongoing need to develop new antimicrobial drugs that are effective against multi-drug-resistant pathogens has spurred the research community to invest in various drug discovery strategies, one of which is drug repurposing—the process of finding new uses for existing drugs. While still nascent in the antimicrobial field, the approach is gaining traction in both the public and private sector. While the approach has particular promise in fast-tracking compounds into clinical studies, it nevertheless has substantial obstacles to success. This Review covers the art of repurposing existing drugs for antimicrobial purposes. We discuss enabling screening platforms for antimicrobial discovery and present encouraging findings of novel antimicrobial therapeutic strategies. Also covered are general advantages of repurposing over de novo drug development and challenges of the strategy, including scientific, intellectual property and regulatory issues.

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Fig. 1: Schematic representation of the regulatory process for licensing conventional versus repurposed compounds.
Fig. 2: Examples of the road to success for some novel antimicrobials identified through repurposing screening campaigns.

References

  1. 1.

    O’Neill, J. Review on Antimicrobial Resistance: tackling a crisis for the health and wealth of nations (HM Government, 2014).

  2. 2.

    Rossolini, G. M., Arena, F., Pecile, P. & Pollini, S. Update on the antibiotic resistance crisis. Curr. Opin. Pharmacol. 18, 56–60 (2014).

    CAS  Article  Google Scholar 

  3. 3.

    Tanwar, J., Das, S., Fatima, Z. & Hameed, S. Multidrug resistance: an emerging crisis. Interdiscip. Perspect. Infect. Dis. 2014, 541340 (2014).

    PubMed  PubMed Central  Google Scholar 

  4. 4.

    Ariey, F. et al. A molecular marker of artemisinin-resistant Plasmodium falciparum malaria. Nature 505, 50–55 (2014).

    PubMed  Google Scholar 

  5. 5.

    Kauffman, C. A., Pappas, P. G. & Patterson, T. F. Fungal infections associated with contaminated methylprednisolone injections. New Engl. J. Med. 368, 2495–2500 (2013).

    CAS  PubMed  Google Scholar 

  6. 6.

    McCarthy, M. Hospital transmitted Candida auris infections confirmed in the US. BMJ 355, i5978 (2016).

    PubMed  Google Scholar 

  7. 7.

    Carroll, M. W. et al. Temporal and spatial analysis of the 2014–2015 Ebola virus outbreak in West Africa. Nature 524, 97–101 (2015).

    CAS  PubMed  Google Scholar 

  8. 8.

    Kreuels, B. et al. A case of severe Ebola virus infection complicated by gram-negative septicemia. New Engl. J. Med. 371, 2394–2401 (2014).

    CAS  PubMed  Google Scholar 

  9. 9.

    Snitkin, E. S. et al. Tracking a hospital outbreak of carbapenem-resistant Klebsiella pneumoniae with whole-genome sequencing. Sci. Transl. Med. 4, 148ra116 (2012).

    PubMed  PubMed Central  Google Scholar 

  10. 10.

    Liu, Y. Y. et al. Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study. Lancet Infect. Dis. 16, 161–168 (2016).

    Google Scholar 

  11. 11.

    Hughes, D. & Karlen, A. Discovery and preclinical development of new antibiotics. Upsala J. Med. Sci. 119, 162–169 (2014).

    PubMed  Google Scholar 

  12. 12.

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

    CAS  Google Scholar 

  13. 13.

    Waring, M. J. et al. An analysis of the attrition of drug candidates from four major pharmaceutical companies. Nat. Rev. Drug Discov. 14, 475–486 (2015).

    CAS  PubMed  Google Scholar 

  14. 14.

    Langedijk, J., Mantel-Teeuwisse, A. K., Slijkerman, D. S. & Schutjens, M. H. Drug repositioning and repurposing: terminology and definitions in literature. Drug Discov. Today 20, 1027–1034 (2015).

    PubMed  Google Scholar 

  15. 15.

    Paolini, G. V., Shapland, R. H., van Hoorn, W. P., Mason, J. S. & Hopkins, A. L. Global mapping of pharmacological space. Nat. Biotechnol. 24, 805–815 (2006).

    CAS  PubMed  Google Scholar 

  16. 16.

    Glicksberg, B. S. et al. An integrative pipeline for multi-modal discovery of disease relationships. Pac. Symp. Biocomput. 20, 407–418 (2015).

    PubMed Central  Google Scholar 

  17. 17.

    Moroney, J. et al. Phase I study of the antiangiogenic antibody bevacizumab and the mTOR/hypoxia-inducible factor inhibitor temsirolimus combined with liposomal doxorubicin: tolerance and biological activity. Clin. Cancer Res. 18, 5796–5805 (2012).

    CAS  PubMed  Google Scholar 

  18. 18.

    Moroney, J. W. et al. A phase I trial of liposomal doxorubicin, bevacizumab, and temsirolimus in patients with advanced gynecologic and breast malignancies. Clin. Cancer Res. 17, 6840–6846 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Ashburn, T. T. & Thor, K. B. Drug repositioning: identifying and developing new uses for existing drugs. Nat. Rev. Drug Discov. 3, 673–683 (2004).

    CAS  PubMed  Google Scholar 

  20. 20.

    Chong, C. R. & Sullivan, D. J. Jr. New uses for old drugs. Nature 448, 645–646 (2007).

    CAS  PubMed  Google Scholar 

  21. 21.

    Norrby, S. R. et al. Lack of development of new antimicrobial drugs: a potential serious threat to public health. Lancet Infect. Dis. 5, 115–119 (2005).

    PubMed  Google Scholar 

  22. 22.

    Kepplinger, E. E. FDA’s expedited approval mechanisms for new drug products. Biotechnol. Law Rep. 34, 15–37 (2015).

    PubMed  PubMed Central  Google Scholar 

  23. 23.

    Hernandez, J. J. et al. Giving drugs a second chance: overcoming regulatory and financial hurdles in repurposing approved drugs as cancer therapeutics. Front. Oncol. 7, 273 (2017).

    PubMed  PubMed Central  Google Scholar 

  24. 24.

    Oprea, T. I. et al. Drug repurposing from an academic perspective. Drug Discov. Today Ther. Strateg. 8, 61–69 (2011).

    PubMed  PubMed Central  Google Scholar 

  25. 25.

    Paul, S. M. et al. How to improve R&D productivity: the pharmaceutical industry’s grand challenge. Nat. Rev. Drug Discov. 9, 203–214 (2010).

    CAS  PubMed  Google Scholar 

  26. 26.

    Oprea, T. I. & Overington, J. P. Computational and practical aspects of drug repositioning. Assay Drug Dev. Techn. 13, 299–306 (2015).

    CAS  Google Scholar 

  27. 27.

    Sun, W., Sanderson, P. E. & Zheng, W. Drug combination therapy increases successful drug repositioning. Drug Discov. Today 21, 1189–1195 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Zeitlinger, M. A. et al. Impact of plasma protein binding on antimicrobial activity using time-killing curves. J. Antimicrob. Chemoth. 54, 876–880 (2004).

    CAS  Google Scholar 

  29. 29.

    Burian, A. et al. Plasma protein binding may reduce antimicrobial activity by preventing intra-bacterial uptake of antibiotics, for example clindamycin. J. Antimicrob. Chemoth. 66, 134–137 (2011).

    CAS  Google Scholar 

  30. 30.

    Schulz, M., Iwersen-Bergmann, S., Andresen, H. & Schmoldt, A. Therapeutic and toxic blood concentrations of nearly 1,000 drugs and other xenobiotics. Crit. Care 16, R136 (2012).

    PubMed  PubMed Central  Google Scholar 

  31. 31.

    Schulz, M. & Schmoldt, A. Therapeutic and toxic blood concentrations of more than 800 drugs and other xenobiotics. Pharmazie 58, 447–474 (2003).

    CAS  PubMed  Google Scholar 

  32. 32.

    Mullard, A. 2013 FDA drug approvals. Nat. Rev. Drug Discov. 13, 85–89 (2014).

    PubMed  Google Scholar 

  33. 33.

    Lin, F. & Wang, S. J. Identification of the factors that result in obviousness rulings for biotech patents: an updated analysis of the US Federal Circuit decisions after KSR. Hum. Vacc. Immunother. 9, 2490–2495 (2013).

    Google Scholar 

  34. 34.

    Wittich, C. M., Burkle, C. M. & Lanier, W. L. Ten common questions (and their answers) about off-label drug use. Mayo Clin. Proc. 87, 982–990 (2012).

    PubMed  PubMed Central  Google Scholar 

  35. 35.

    Morello, L. More cuts loom for US science. Nature 501, 147–148 (2013).

    CAS  PubMed  Google Scholar 

  36. 36.

    Pantziarka, P. et al. The repurposing drugs in oncology (ReDO) project. eCancermedicalscience 8, 442 (2014).

    PubMed  PubMed Central  Google Scholar 

  37. 37.

    Issa, N. T., Kruger, J., Byers, S. W. & Dakshanamurthy, S. Drug repurposing a reality: from computers to the clinic. Expert Rev. Clin. Pharm. 6, 95–97 (2013).

    CAS  Google Scholar 

  38. 38.

    Bessoff, K., Sateriale, A., Lee, K. K. & Huston, C. D. Drug repurposing screen reveals FDA-approved inhibitors of human HMG-CoA reductase and isoprenoid synthesis that block Cryptosporidium parvum growth. Antimicrob. Agents Ch. 57, 1804–1814 (2013).

    CAS  Google Scholar 

  39. 39.

    Debnath, A. et al. A high-throughput drug screen for Entamoeba histolytica identifies a new lead and target. Nat. Med. 18, 956–960 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Lucumi, E. et al. Discovery of potent small-molecule inhibitors of multidrug-resistant Plasmodium falciparum using a novel miniaturized high-throughput luciferase-based assay. Antimicrob. Agents Ch. 54, 3597–3604 (2010).

    CAS  Google Scholar 

  41. 41.

    da Cruz, F. P. et al. Drug screen targeted at Plasmodium liver stages identifies a potent multistage antimalarial drug. J. Infect. Dis. 205, 1278–1286 (2012).

    PubMed  PubMed Central  Google Scholar 

  42. 42.

    Chong, C. R., Chen, X., Shi, L., Liu, J. O. & Sullivan, D. J. Jr. A clinical drug library screen identifies astemizole as an antimalarial agent. Nat. Chem. Biol. 2, 415–416 (2006).

    CAS  PubMed  Google Scholar 

  43. 43.

    Chen, C. Z. et al. High-throughput Giardia lamblia viability assay using bioluminescent ATP content measurements. Antimicrob. Agents Ch. 55, 667–675 (2011).

    CAS  Google Scholar 

  44. 44.

    Chockalingam, K., Simeon, R. L., Rice, C. M. & Chen, Z. A cell protection screen reveals potent inhibitors of multiple stages of the hepatitis C virus life cycle. Proc. Natl Acad. Sci. USA 107, 3764–3769 (2010).

    CAS  PubMed  Google Scholar 

  45. 45.

    Dyall, J. et al. Repurposing of clinically developed drugs for treatment of Middle East respiratory syndrome coronavirus infection. Antimicrob. Agents Ch. 58, 4885–4893 (2014).

    Google Scholar 

  46. 46.

    Gastaminza, P., Whitten-Bauer, C. & Chisari, F. V. Unbiased probing of the entire hepatitis C virus life cycle identifies clinical compounds that target multiple aspects of the infection. Proc. Natl Acad. Sci. USA 107, 291–296 (2010).

    CAS  PubMed  Google Scholar 

  47. 47.

    He, S. et al. Repurposing of the antihistamine chlorcyclizine and related compounds for treatment of hepatitis C virus infection. Sci. Transl Med. 7, 282ra249 (2015).

    Google Scholar 

  48. 48.

    Madrid, P. B. et al. Evaluation of Ebola virus inhibitors for drug repurposing. ACS Infect. Dis. 1, 317–326 (2015).

    CAS  PubMed  Google Scholar 

  49. 49.

    Johansen, L. M. et al. A screen of approved drugs and molecular probes identifies therapeutics with anti-Ebola virus activity. Sci. Transl Med. 7, 290ra289 (2015).

    Google Scholar 

  50. 50.

    Kouznetsova, J. et al. Identification of 53 compounds that block Ebola virus-like particle entry via a repurposing screen of approved drugs. Emerg. Microbes Infect. 3, e84 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Barrows, N. J. et al. A screen of FDA-approved drugs for inhibitors of Zika virus infection. Cell Host Microbe 20, 259–270 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Butts, A. et al. A repurposing approach identifies off-patent drugs with fungicidal cryptococcal activity, a common structural chemotype, and pharmacological properties relevant to the treatment of cryptococcosis. Eukaryot. Cell 12, 278–287 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Krysan, D. J. & Didone, L. A high-throughput screening assay for small molecules that disrupt yeast cell integrity. J. Biomol. Screen. 13, 657–664 (2008).

    CAS  PubMed  Google Scholar 

  54. 54.

    Siles, S. A., Srinivasan, A., Pierce, C. G., Lopez-Ribot, J. L. & Ramasubramanian, A. K. High-throughput screening of a collection of known pharmacologically active small compounds for identification of Candida albicans biofilm inhibitors. Antimicrob. Agents Ch. 57, 3681–3687 (2013).

    CAS  Google Scholar 

  55. 55.

    Zhai, B. et al. Polymyxin B, in combination with fluconazole, exerts a potent fungicidal effect. J. Antimicrob. Chemoth. 65, 931–938 (2010).

    CAS  Google Scholar 

  56. 56.

    Chopra, S. et al. Repurposing FDA-approved drugs to combat drug-resistant Acinetobacter baumannii. J. Antimicrob. Chemoth 65, 2598–2601 (2010).

    CAS  Google Scholar 

  57. 57.

    Jacobs, A. C. et al. Adenylate kinase release as a high-throughput-screening-compatible reporter of bacterial lysis for identification of antibacterial agents. Antimicrob. Agents Ch. 57, 26–36 (2013).

    CAS  Google Scholar 

  58. 58.

    Pothineni, V. R. et al. Identification of new drug candidates against Borrelia burgdorferi using high-throughput screening. Drug Des. Dev. Ther. 10, 1307–1322 (2016).

    CAS  Google Scholar 

  59. 59.

    Sun, W. et al. Rapid antimicrobial susceptibility test for identification of new therapeutics and drug combinations against multidrug-resistant bacteria. Emerg. Microbes Infec. 5, e116 (2016).

    CAS  Google Scholar 

  60. 60.

    Younis, W., Thangamani, S. & Seleem, M. N. Repurposing non-antimicrobial drugs and clinical molecules to treat bacterial infections. Curr. Pharm. Design 21, 4106–4111 (2015).

    CAS  Google Scholar 

  61. 61.

    Schenone, M., Dancik, V., Wagner, B. K. & Clemons, P. A. Target identification and mechanism of action in chemical biology and drug discovery. Nat. Chem. Biol. 9, 232–240 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Zheng, W., Thorne, N. & McKew, J. C. Phenotypic screens as a renewed approach for drug discovery. Drug Discov. Today 18, 1067–1073 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Gregori-Puigjane, E. et al. Identifying mechanism-of-action targets for drugs and probes. Proc. Natl Acad. Sci. USA 109, 11178–11183 (2012).

    CAS  PubMed  Google Scholar 

  64. 64.

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

    PubMed  Google Scholar 

  65. 65.

    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).

    CAS  PubMed  Google Scholar 

  66. 66.

    Stokes, J. M., Davis, J. H., Mangat, C. S., Williamson, J. R. & Brown, E. D. Discovery of a small molecule that inhibits bacterial ribosome biogenesis. eLife 3, e03574 (2014).

    PubMed  PubMed Central  Google Scholar 

  67. 67.

    Xu, M. et al. Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen. Nat. Med. 22, 1101–1107 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68.

    Imperi, F. et al. Repurposing the antimycotic drug flucytosine for suppression of Pseudomonas aeruginosa pathogenicity. Proc. Natl Acad. Sci. USA 110, 7458–7463 (2013).

    CAS  PubMed  Google Scholar 

  69. 69.

    Imperi, F. et al. New life for an old drug: the anthelmintic drug niclosamide inhibits Pseudomonas aeruginosa quorum sensing. Antimicrob. Agents Ch. 57, 996–1005 (2013).

    CAS  Google Scholar 

  70. 70.

    Engel, J. C. et al. Image-based high-throughput drug screening targeting the intracellular stage of Trypanosoma cruzi, the agent of Chagas’ disease. Antimicrob. Agents Ch. 54, 3326–3334 (2010).

    CAS  Google Scholar 

  71. 71.

    Breger, J. et al. Antifungal chemical compounds identified using a C. elegans pathogenicity assay. PLoS Pathog. 3, e18 (2007).

    PubMed  PubMed Central  Google Scholar 

  72. 72.

    Rajamuthiah, R. et al. Whole animal automated platform for drug discovery against multi-drug resistant Staphylococcus aureus. PLoS ONE 9, e89189 (2014).

    PubMed  PubMed Central  Google Scholar 

  73. 73.

    Brown, S. A., Palmer, K. L. & Whiteley, M. Revisiting the host as a growth medium. Nat. Rev. Microbiol. 6, 657–666 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74.

    Colquhoun, J. M., Wozniak, R. A. & Dunman, P. M. Clinically relevant growth conditions alter Acinetobacter baumannii antibiotic susceptibility and promote identification of novel antibacterial agents. PLoS ONE 10, e0143033 (2015).

    PubMed  PubMed Central  Google Scholar 

  75. 75.

    Andersson, J. A. et al. New role for FDA-approved drugs in combating antibiotic-resistant bacteria. Antimicrob. Agents Ch. 60, 3717–3729 (2016).

    CAS  Google Scholar 

  76. 76.

    Czyz, D. M. et al. Host-directed antimicrobial drugs with broad-spectrum efficacy against intracellular bacterial pathogens. mBio. 5, e01534–01514 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Singh, S. B. Confronting the challenges of discovery of novel antibacterial agents. Bioorg. Med. Chem. Lett. 24, 3683–3689 (2014).

    CAS  PubMed  Google Scholar 

  78. 78.

    Ejim, L. et al. Combinations of antibiotics and nonantibiotic drugs enhance antimicrobial efficacy. Nat. Chem. Biol. 7, 348–350 (2011).

    CAS  PubMed  Google Scholar 

  79. 79.

    Spitzer, M. et al. Cross-species discovery of syncretic drug combinations that potentiate the antifungal fluconazole. Mol. Syst. Biol. 7, 499 (2011).

    PubMed  PubMed Central  Google Scholar 

  80. 80.

    Planer, J. D. et al. Synergy testing of FDA-approved drugs identifies potent drug combinations against Trypanosoma cruzi. PLoS Neglect. Trop. D. 8, e2977 (2014).

    Google Scholar 

  81. 81.

    Sun, W. et al. Synergistic drug combination effectively blocks Ebola virus infection. Antivir. Res. 137, 165–172 (2017).

    CAS  PubMed  Google Scholar 

  82. 82.

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

    CAS  PubMed  Google Scholar 

  83. 83.

    Aeschlimann, J. R., Dresser, L. D., Kaatz, G. W. & Rybak, M. J. Effects of NorA inhibitors on in vitro antibacterial activities and postantibiotic effects of levofloxacin, ciprofloxacin, and norfloxacin in genetically related strains of Staphylococcus aureus. Antimicrob. Agents Ch. 43, 335–340 (1999).

    CAS  Google Scholar 

  84. 84.

    Van den Driessche, F., Brackman, G., Swimberghe, R., Rigole, P. & Coenye, T. Screening a repurposing library for potentiators of antibiotics against Staphylococcus aureus biofilms. Int. J. Antimicrob. Ag. 49, 315–320 (2017).

    Google Scholar 

  85. 85.

    Delattin, N. et al. Repurposing as a means to increase the activity of amphotericin B and caspofungin against Candida albicans biofilms. J. Antimicrob. Chemoth. 69, 1035–1044 (2014).

    CAS  Google Scholar 

  86. 86.

    Stokes, J. M. et al. Pentamidine sensitizes Gram-negative pathogens to antibiotics and overcomes acquired colistin resistance. Nat. Microbiol. 2, 17028 (2017).

    PubMed  PubMed Central  Google Scholar 

  87. 87.

    Lehar, J. et al. Synergistic drug combinations tend to improve therapeutically relevant selectivity. Nat. Biotechnol. 27, 659–666 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88.

    Delcour, A. H. Outer membrane permeability and antibiotic resistance. Biochim. Biophys. Acta. 1794, 808–816 (2009).

    CAS  PubMed  Google Scholar 

  89. 89.

    MacNair, C. R. et al. Overcoming mcr-1 mediated colistin resistance with colistin in combination with other antibiotics. Nat. Commun. 9, 458 (2018).

    PubMed  PubMed Central  Google Scholar 

  90. 90.

    Gygli, S. M., Borrell, S., Trauner, A. & Gagneux, S. Antimicrobial resistance in Mycobacterium tuberculosis: mechanistic and evolutionary perspectives. FEMS Microbiol. Rev. 41, 354–373 (2017).

    CAS  PubMed  Google Scholar 

  91. 91.

    Bollenbach, T. Antimicrobial interactions: mechanisms and implications for drug discovery and resistance evolution. Curr. Opin. Microbiol. 27, 1–9 (2015).

    CAS  PubMed  Google Scholar 

  92. 92.

    Eliopoulos, G. M. & Moellering, R. C. Jr. Antibiotic synergism and antimicrobial combinations in clinical infections. Rev. Infect. Dis. 4, 282–293 (1982).

    CAS  PubMed  Google Scholar 

  93. 93.

    Bonhoeffer, S., Lipsitch, M. & Levin, B. R. Evaluating treatment protocols to prevent antibiotic resistance. Proc. Natl Acad. Sci. USA 94, 12106–12111 (1997).

    CAS  PubMed  Google Scholar 

  94. 94.

    Mouton, J. W. Combination therapy as a tool to prevent emergence of bacterial resistance. Infection 27, S24–S28 (1999).

    PubMed  Google Scholar 

  95. 95.

    Torella, J. P., Chait, R. & Kishony, R. Optimal drug synergy in antimicrobial treatments. PLoS Comput. Biol. 6, e1000796 (2010).

    PubMed  PubMed Central  Google Scholar 

  96. 96.

    Worthington, R. J. & Melander, C. Combination approaches to combat multidrug-resistant bacteria. Trends Biotechnol. 31, 177–184 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97.

    Kinnings, S. L. et al. Drug discovery using chemical systems biology: repositioning the safe medicine Comtan to treat multi-drug and extensively drug resistant tuberculosis. PLoS Comput. Biol. 5, e1000423 (2009).

    PubMed  PubMed Central  Google Scholar 

  98. 98.

    Forsberg, M. et al. Pharmacokinetics and pharmacodynamics of entacapone and tolcapone after acute and repeated administration: a comparative study in the rat. J. Pharmacol. Exp. Ther. 304, 498–506 (2003).

    CAS  PubMed  Google Scholar 

  99. 99.

    Khodaverdian, V. et al. Discovery of antivirulence agents against methicillin-resistant Staphylococcus aureus. Antimicrob. Agents Ch. 57, 3645–3652 (2013).

    CAS  Google Scholar 

  100. 100.

    Astolfi, A. et al. Pharmacophore-based repositioning of approved drugs as novel Staphylococcus aureus NorA efflux pump inhibitors. J. Med. Chem. 60, 1598–1604 (2017).

    CAS  PubMed  Google Scholar 

  101. 101.

    Carlson-Banning, K. M. et al. Toward repurposing ciclopirox as an antibiotic against drug-resistant Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumoniae. PLoS ONE 8, e69646 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102.

    Deng, L., Sundriyal, S., Rubio, V., Shi, Z. Z. & Song, Y. Coordination chemistry based approach to lipophilic inhibitors of 1-deoxy-D-xylulose-5-phosphate reductoisomerase. J Med. Chem. 52, 6539–6542 (2009).

    CAS  PubMed  Google Scholar 

  103. 103.

    Ekins, S., Mestres, J. & Testa, B. In silico pharmacology for drug discovery: methods for virtual ligand screening and profiling. Brit. J. Pharmacol. 152, 9–20 (2007).

    CAS  Google Scholar 

  104. 104.

    Wang, Y. et al. PubChem BioAssay: 2014 update. Nucleic Acids Res. 42, D1075–D1082 (2014).

    CAS  PubMed  Google Scholar 

  105. 105.

    Wishart, D. S. et al. DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 36, D901–D906 (2008).

    CAS  PubMed  Google Scholar 

  106. 106.

    Bento, A. P. et al. The ChEMBL bioactivity database: an update. Nucleic Acids Res. 42, D1083–D1090 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107.

    Brown, A. S. & Patel, C. J. A standard database for drug repositioning. Sci. Data 4, 170029 (2017).

    PubMed  PubMed Central  Google Scholar 

  108. 108.

    Shameer, K. et al. Systematic analyses of drugs and disease indications in RepurposeDB reveal pharmacological, biological and epidemiological factors influencing drug repositioning. Brief Bioinform. 19, 656–678 (2017).

    PubMed Central  Google Scholar 

  109. 109.

    Sateriale, A., Bessoff, K., Sarkar, I. N. & Huston, C. D. Drug repurposing: mining protozoan proteomes for targets of known bioactive compounds. J. Am. Med. Inform. Assn. 21, 238–244 (2014).

    Google Scholar 

  110. 110.

    Chavali, A. K. et al. Metabolic network analysis predicts efficacy of FDA-approved drugs targeting the causative agent of a neglected tropical disease. BMC Syst. Biol. 6, 27 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 111.

    Lamb, J. The Connectivity Map: a new tool for biomedical research. Nat. Rev. Cancer 7, 54–60 (2007).

    CAS  PubMed  Google Scholar 

  112. 112.

    Josset, L. et al. Gene expression signature-based screening identifies new broadly effective influenza a antivirals. PLoS ONE 5, e13169 (2010).

    PubMed  PubMed Central  Google Scholar 

  113. 113.

    Coelho, E. D., Arrais, J. P. & Oliveira, J. L. Computational discovery of putative leads for drug repositioning through drug-target interaction prediction. PLoS Comput. Biol. 12, e1005219 (2016).

    PubMed  PubMed Central  Google Scholar 

  114. 114.

    Berenstein, A. J., Magarinos, M. P., Chernomoretz, A. & Aguero, F. A multilayer network approach for guiding drug repositioning in neglected diseases. PLoS Negl. Trop. D. 10, e0004300 (2016).

    Google Scholar 

  115. 115.

    Iwata, H., Sawada, R., Mizutani, S. & Yamanishi, Y. Systematic drug repositioning for a wide range of diseases with integrative analyses of phenotypic and molecular data. J. Chem. Inf. Model. 55, 446–459 (2015).

    CAS  PubMed  Google Scholar 

  116. 116.

    Malo, N., Hanley, J. A., Cerquozzi, S., Pelletier, J. & Nadon, R. Statistical practice in high-throughput screening data analysis. Nat. Biotechnol. 24, 167–175 (2006).

    CAS  PubMed  Google Scholar 

  117. 117.

    Li, Y. Y. & Jones, S. J. Drug repositioning for personalized medicine. Genome Med. 4, 27 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118.

    March-Vila, E. et al. On the integration of in silico drug design methods for drug repurposing. Front. Pharmacol. 8, 298 (2017).

    PubMed  PubMed Central  Google Scholar 

  119. 119.

    Meyerhoff, A. U. S. Food and Drug Administration approval of AmBisome (liposomal amphotericin B) for treatment of visceral leishmaniasis. Clin. Infect. Dis. 28, 42–48 (1999). discussion 49–51.

    CAS  PubMed  Google Scholar 

  120. 120.

    Cohen, H. G. & Reynolds, T. B. Comparison of metronidazole and chloroquine for the treatment of amoebic liver abscess. A controlled trial. Gastroenterology 69, 35–41 (1975).

    CAS  PubMed  Google Scholar 

  121. 121.

    Katlama, C., De Wit, S., O’Doherty, E., Van Glabeke, M. & Clumeck, N. Pyrimethamine-clindamycin vs. pyrimethamine-sulfadiazine as acute and long-term therapy for toxoplasmic encephalitis in patients with AIDS. Clin. Infect. Dis. 22, 268–275 (1996).

    CAS  PubMed  Google Scholar 

  122. 122.

    Tan, K. R. et al. Doxycycline for malaria chemoprophylaxis and treatment: report from the CDC expert meeting on malaria chemoprophylaxis. Am. J. Trop. Med. Hyg. 84, 517–531 (2011).

    PubMed  PubMed Central  Google Scholar 

  123. 123.

    Ben Salah, A. et al. Topical paromomycin with or without gentamicin for cutaneous leishmaniasis. New Engl. J. Med. 368, 524–532 (2013).

    PubMed  Google Scholar 

  124. 124.

    Robert-Gangneux, F. & Darde, M. L. Epidemiology of and diagnostic strategies for toxoplasmosis. Clin. Microbiol. Rev. 25, 264–296 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 125.

    Medina-Franco, J. L., Giulianotti, M. A., Welmaker, G. S. & Houghten, R. A. Shifting from the single to the multitarget paradigm in drug discovery. Drug Discov. Today 18, 495–501 (2013).

    PubMed  PubMed Central  Google Scholar 

  126. 126.

    Fairlamb, A. H., Gow, N. A., Matthews, K. R. & Waters, A. P. Drug resistance in eukaryotic microorganisms. Nat. Microbiol. 1, 16092 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. 127.

    Weisman, J. L. et al. Searching for new antimalarial therapeutics amongst known drugs. Chem. Biol. Drug Des. 67, 409–416 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. 128.

    World malaria report 2017 (WHO, 2017).

  129. 129.

    Attaran, A. Where did it all go wrong? Nature 430, 932–933 (2004).

    CAS  PubMed  Google Scholar 

  130. 130.

    Gottlieb, S. Antihistamine drug withdrawn by manufacturer. BMJ 319, 7 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. 131.

    Derbyshire, E. R., Prudencio, M., Mota, M. M. & Clardy, J. Liver-stage malaria parasites vulnerable to diverse chemical scaffolds. Proc. Natl Acad. Sci. USA 109, 8511–8516 (2012).

    CAS  PubMed  Google Scholar 

  132. 132.

    Roman, G., Crandall, I. E. & Szarek, W. A. Synthesis and anti-Plasmodium activity of benzimidazole analogues structurally related to astemizole. ChemMedChem 8, 1795–1804 (2013).

    CAS  PubMed  Google Scholar 

  133. 133.

    Gunther, J., Shafir, S., Bristow, B. & Sorvillo, F. Short report: Amebiasis-related mortality among United States residents, 1990–2007. Am. J. Trop. Med. Hyg. 85, 1038–1040 (2011).

    PubMed  PubMed Central  Google Scholar 

  134. 134.

    Andrade, R. M. & Reed, S. L. New drug target in protozoan parasites: the role of thioredoxin reductase. Front. Microbiol. 6, 975 (2015).

    PubMed  PubMed Central  Google Scholar 

  135. 135.

    Roder, C. & Thomson, M. J. Auranofin: repurposing an old drug for a golden new age. Drugs R.D. 15, 13–20 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. 136.

    Tejman-Yarden, N. et al. A reprofiled drug, auranofin, is effective against metronidazole-resistant Giardia lamblia. Antimicrob. Agents Ch. 57, 2029–2035 (2013).

    CAS  Google Scholar 

  137. 137.

    Berglof, F. E., Berglof, K. & Walz, D. T. Auranofin: an oral chrysotherapeutic agent for the treatment of rheumatoid arthritis. J. Rheumatol. 5, 68–74 (1978).

    CAS  PubMed  Google Scholar 

  138. 138.

    Hill, A. & Cooke, G. Medicine. Hepatitis C can be cured globally, but at what cost? Science 345, 141–142 (2014).

    CAS  PubMed  Google Scholar 

  139. 139.

    Huang, R. et al. The NCGC pharmaceutical collection: a comprehensive resource of clinically approved drugs enabling repurposing and chemical genomics. Sci. Transl Med. 3, 80ps16 (2011).

    PubMed  PubMed Central  Google Scholar 

  140. 140.

    Chen, L. H. & Hamer, D. H. Zika virus: rapid spread in the Western hemisphere. Ann. Intern. Med. 164, 613–615 (2016).

    PubMed  Google Scholar 

  141. 141.

    Tang, H. et al. Zika virus infects human cortical neural progenitors and attenuates their growth. Cell Stem Cell 18, 587–590 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. 142.

    Khanim, F. L. et al. Redeployment-based drug screening identifies the anti-helminthic niclosamide as anti-myeloma therapy that also reduces free light chain production. Blood Cancer J. 1, e39 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. 143.

    Jordan, V. C. Tamoxifen: the herald of a new era of preventive therapeutics. J. Natl Cancer I. 89, 747–749 (1997).

    CAS  Google Scholar 

  144. 144.

    Friedman, Z. Y. Recent advances in understanding the molecular mechanisms of tamoxifen action. Cancer Invest. 16, 391–396 (1998).

    CAS  PubMed  Google Scholar 

  145. 145.

    Dolan, K. et al. Antifungal activity of tamoxifen: in vitro and in vivo activities and mechanistic characterization. Antimicrob. Agents Ch. 53, 3337–3346 (2009).

    CAS  Google Scholar 

  146. 146.

    Wiseman, H., Cannon, M. & Arnstein, H. R. Observation and significance of growth inhibition of Saccharomyces cerevisiae (A224A) by the anti-oestrogen drug tamoxifen. Biochem. Soc. T. 17, 1038–1039 (1989).

    CAS  Google Scholar 

  147. 147.

    Wiseman, H., Cannon, M., Arnstein, H. R. & Halliwell, B. Enhancement by tamoxifen of the membrane antioxidant action of the yeast membrane sterol ergosterol: relevance to the antiyeast and anticancer action of tamoxifen. Biochim. Biophys. Acta 1181, 201–206 (1993).

    CAS  PubMed  Google Scholar 

  148. 148.

    Beggs, W. H. Anti-Candida activity of the anti-cancer drug tamoxifen. Res. Commun. Chem. Path. 80, 125–128 (1993).

    CAS  Google Scholar 

  149. 149.

    Edlind, T., Smith, L., Henry, K., Katiyar, S. & Nickels, J. Antifungal activity in Saccharomyces cerevisiae is modulated by calcium signalling. Mol. Microbiol. 46, 257–268 (2002).

    CAS  PubMed  Google Scholar 

  150. 150.

    Parsons, A. B. et al. Exploring the mode-of-action of bioactive compounds by chemical-genetic profiling in yeast. Cell 126, 611–625 (2006).

    CAS  PubMed  Google Scholar 

  151. 151.

    Antimisiaris, D., Bae, K. G., Morton, L. & Gully, Z. Tamoxifen pharmacovigilance: implications for safe use in the future. Consult. Pharm. 32, 535–546 (2017).

    PubMed  PubMed Central  Google Scholar 

  152. 152.

    Lass-Florl, C., Dierich, M. P., Fuchs, D., Semenitz, E. & Ledochowski, M. Antifungal activity against Candida species of the selective serotonin-reuptake inhibitor, sertraline. Clin. Infect. Dis. 33, E135–E136 (2001).

    CAS  PubMed  Google Scholar 

  153. 153.

    Lass-Florl, C. et al. Antifungal properties of selective serotonin reuptake inhibitors against Aspergillus species in vitro. J. Antimicrob. Chemoth. 48, 775–779 (2001).

    CAS  Google Scholar 

  154. 154.

    Zhai, B., Wu, C., Wang, L., Sachs, M. S. & Lin, X. The antidepressant sertraline provides a promising therapeutic option for neurotropic cryptococcal infections. Antimicrob. Agents Ch. 56, 3758–3766 (2012).

    CAS  Google Scholar 

  155. 155.

    Rhein, J. et al. Efficacy of adjunctive sertraline for the treatment of HIV-associated cryptococcal meningitis: an open-label dose-ranging study. Lancet Infect. Dis. 16, 809–818 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. 156.

    Villanueva-Lozano, H. et al. Clinical evaluation of the antifungal effect of sertraline in the treatment of cryptococcal meningitis in HIV patients: a single Mexican center experience. Infection 46, 25–30 (2018).

    CAS  PubMed  Google Scholar 

  157. 157.

    Andrews, P., Thyssen, J. & Lorke, D. The biology and toxicology of molluscicides, Bayluscide. Pharmacol. Therapeut. 19, 245–295 (1982).

    CAS  Google Scholar 

  158. 158.

    Mook, R. A. Jr et al. Structure-activity studies of Wnt/beta-catenin inhibition in the Niclosamide chemotype: identification of derivatives with improved drug exposure. Bioorgan. Med. Chem. 23, 5829–5838 (2015).

    CAS  Google Scholar 

  159. 159.

    Ye, Y., Zhang, X., Zhang, T., Wang, H. & Wu, B. Design and evaluation of injectable niclosamide nanocrystals prepared by wet media milling technique. Drug Dev. Ind. Pharm. 41, 1416–1424 (2015).

    CAS  PubMed  Google Scholar 

  160. 160.

    Lu, W. et al. Niclosamide suppresses cancer cell growth by inducing Wnt co-receptor LRP6 degradation and inhibiting the Wnt/beta-catenin pathway. PLoS ONE 6, e29290 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. 161.

    Li, R. et al. Niclosamide overcomes acquired resistance to erlotinib through suppression of STAT3 in non-small cell lung cancer. Mol. Cancer Ther. 12, 2200–2212 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. 162.

    Liang, L. et al. Inhibitory effects of niclosamide on inflammation and migration of fibroblast-like synoviocytes from patients with rheumatoid arthritis. Inflamm. Res. 64, 225–233 (2015).

    CAS  PubMed  Google Scholar 

  163. 163.

    Jurgeit, A. et al. Niclosamide is a proton carrier and targets acidic endosomes with broad antiviral effects. PLoS Pathog. 8, e1002976 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. 164.

    Amos, H. & Vollmayer, E. Effect of pentamidine on the growth of Escherichia coli. J. Bacteriol. 73, 172–177 (1957).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. 165.

    Wien, R., Harrison, J. & Freeman, W. A. Diamidines as antibacterial compounds. Brit. J. Pharm. Chemoth. 3, 211–218 (1948).

    CAS  Google Scholar 

  166. 166.

    Wien, R., Harrison, J. & Freeman, W. A. New antibacterial diamidines. Lancet 1, 711 (1948).

    CAS  PubMed  Google Scholar 

  167. 167.

    Libman, M. D., Miller, M. A. & Richards, G. K. Antistaphylococcal activity of pentamidine. Antimicrob. Agents Ch. 34, 1795–1796 (1990).

    CAS  Google Scholar 

  168. 168.

    Fox, K. R., Sansom, C. E. & Stevens, M. F. Footprinting studies on the sequence-selective binding of pentamidine to DNA. FEBS Lett. 266, 150–154 (1990).

    CAS  PubMed  Google Scholar 

  169. 169.

    Minnick, M. F., Hicks, L. D., Battisti, J. M. & Raghavan, R. Pentamidine inhibits Coxiella burnetii growth and 23S rRNA intron splicing in vitro. Int. J. Antimicrob. Ag. 36, 380–382 (2010).

    CAS  Google Scholar 

  170. 170.

    Sun, T. & Zhang, Y. Pentamidine binds to tRNA through non-specific hydrophobic interactions and inhibits aminoacylation and translation. Nucleic Acids Res. 36, 1654–1664 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. 171.

    Mullard, A. Drug repurposing programmes get lift off. Nat. Rev. Drug Discov. 11, 505–506 (2012).

    CAS  PubMed  Google Scholar 

  172. 172.

    Corsello, S. M. et al. The Drug Repurposing Hub: a next-generation drug library and information resource. Nat. Med. 23, 405–408 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. 173.

    Weir, S. J., DeGennaro, L. J. & Austin, C. P. Repurposing approved and abandoned drugs for the treatment and prevention of cancer through public-private partnership. Cancer Res. 72, 1055–1058 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. 174.

    Kwok, A. K. & Koenigbauer, F. M. Incentives to repurpose existing drugs for orphan indications. ACS Med. Chem. Lett. 6, 828–830 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  175. 175.

    Simarro, P. P., Franco, J., Diarra, A., Postigo, J. A. & Jannin, J. Update on field use of the available drugs for the chemotherapy of human African trypanosomiasis. Parasitology 139, 842–846 (2012).

    CAS  PubMed  Google Scholar 

  176. 176.

    Smorenburg, C. H. et al. Phase II study of miltefosine 6% solution as topical treatment of skin metastases in breast cancer patients. Colloq. Inse. 11, 825–828 (2000).

    CAS  Google Scholar 

  177. 177.

    Yarchoan, R. et al. Administration of 3’-azido-3’-deoxythymidine, an inhibitor of HTLV-III/LAV replication, to patients with AIDS or AIDS-related complex. Lancet 1, 575–580 (1986).

    CAS  PubMed  Google Scholar 

  178. 178.

    Simpson, P. B. & Reichman, M. Opening the lead generation toolbox. Nat. Rev. Drug Discov. 13, 3–4 (2014).

    CAS  PubMed  Google Scholar 

  179. 179.

    Nilsson, N. & Felding, J. Open innovation platforms to boost pharmaceutical collaborations: evaluating external compounds for desired biological activity. Future Med. Chem. 7, 1853–1859 (2015).

    CAS  PubMed  Google Scholar 

  180. 180.

    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 Deliver. Rev. 46, 3–26 (2001).

    CAS  Google Scholar 

  181. 181.

    Magarinos, M. P. et al. TDR Targets: a chemogenomics resource for neglected diseases. Nucleic Acids Res. 40, D1118–D1127 (2012).

    CAS  PubMed  Google Scholar 

  182. 182.

    von Eichborn, J. et al. PROMISCUOUS: a database for network-based drug-repositioning. Nucleic Acids Res. 39, D1060–D1066 (2011).

    Google Scholar 

  183. 183.

    Kuhn, M., Letunic, I., Jensen, L. J. & Bork, P. The SIDER database of drugs and side effects. Nucleic Acids Res. 44, D1075–D1079 (2016).

    CAS  PubMed  Google Scholar 

  184. 184.

    Siramshetty, V. B. et al. SuperDRUG2: a one stop resource for approved/marketed drugs. Nucleic Acids Res. 46, D1137–D1143 (2018).

    CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by a Foundation grant from the Canadian Institutes of Health Research (FRN-143215) and a Tier I Canada Research Chair award to E.D.B.

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Farha, M.A., Brown, E.D. Drug repurposing for antimicrobial discovery. Nat Microbiol 4, 565–577 (2019). https://doi.org/10.1038/s41564-019-0357-1

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