Skip to main content
SpringerLink
Log in

Impediments to Discovery of New Antimicrobials with New Modes of Action

  • Chapter
  • First Online:
Antibacterial Drug Discovery to Combat MDR

  • 945 Accesses

Abstract

During the golden age of antibiotic discovery (1945–1970), little thought was given to the possibility that someday we would run out of them. It is shocking to admit that the last class of antibiotics was discovered over 30 years ago. What happened? The easy answer is that discovering new antibiotics is really hard, developing them is even harder, and once you get them to the clinic, there is little economic value for your efforts. This chapter seeks to explain some of the impediments to discovery of new antibiotics that include (1) the number of potential broad-spectrum “common” drug targets is small; (2) new pharmacophores are prone to early failure due to cytotoxicity, drug metabolism, or poor pharmacokinetics; (3) the general reticence to embrace and apply new technologies; (4) societal issues associated with their use and costs; and (5) the general lack of grant funding to support early discovery efforts. Despite these strong head winds, several concepts and approaches are discussed along with examples of what is working.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Ballard, T. E., Wang, X., Olekhnovich, I., Koerner, T., Seymour, C., Salamoun, J., Warthan, M., Hoffman, P. S., & Macdonald, T. L. (2011). Synthesis and antimicrobial evaluation of nitazoxanide-based analogues: Identification of selective and broad spectrum activity. Chem Med Chem, 6, 362–377.

    Article  CAS  PubMed  Google Scholar 

  • Berube, B. J., Murphy, K. R., Torhan, M. C., Bowlin, N. O., Williams, J. D., Bowlin, T. L., Moir, D. T., & Hauser, A. R. (2017). Impact of type III secretion effectors and of phenoxyacetamide inhibitors of type III secretion on abscess formation in a mouse model of Pseudomonas aeruginosa infection. Antimicrobial Agents and Chemotherapy, 61(11), pii: e01202–17.

    Article  Google Scholar 

  • Boucher, H. W., Talbot, G. H., Bradley, J. S., Edwards, J. E., Gilbert, D., Rice, L. B., Scheld, M., Spellberg, B., & Bartlett, J. (2009). Bad bugs, no drugs: no ESKAPE! an update from the Infectious Diseases Society of America. Clinical Infectious Diseases, 48, 1–12.

    Article  PubMed  Google Scholar 

  • Bush, K., & Bradford, P. A. (2016). β-Lactams and β-Lactamase inhibitors: An overview. Cold Spring Harbor Perspectives in Medicine, 6(8), pii: a025247.

    Article  Google Scholar 

  • Chahales, P., Hoffman, P. S., & Thanassi, D. G. (2016). Nitazoxanide inhibits pilus biogenesis by interfering with folding of the usher protein in the outer membrane. Antimicrobial Agents and Chemotherapy, 60(4), 2028–2038.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chalker, A. F., Minehart, H. W., Hughes, N. J., Koretke, K. K., Brown, J. R., Lonetto, M. A., Warren, P. V., Stanhope, M. J., Lupas, A., & Hoffman, P. S. (2001). Systematic identification of unique essential genes in Helicobacter pylori by genome prioritization and allelic replacement mutagenesis. Journal of Bacteriology, 183, 1259–1268.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chaudhary, A. S. (2016). A review of global initiatives to fight antibiotic resistance and recent antibiotics′ discovery. Acta Pharmaceutica Sinica B, 6, 552–556.

    Article  PubMed  PubMed Central  Google Scholar 

  • Cole, S. T. (2014). Who will develop new antibacterial agents? Philosophical Transactions of the Royal Society B, 369, 20130430. https://doi.org/10.1098/rstb.2013.0430.

    Article  Google Scholar 

  • D’Ari, R., & Casadesus, J. (1998). Underground metabolism. BioEssays, 20, 181–186.

    Article  PubMed  Google Scholar 

  • Devasahayam, G., Scheld, W. M., & Hoffman, P. S. (2010). Newer antibacterial drugs for a new century. Expert Opinion, 19, 1–20.

    Google Scholar 

  • Dickey, S. W., Cheung, G. Y. C., & Otto, M. (2017). Different drugs for bad bugs: Antivirulence strategies in the age of antibiotic resistance. Nature Reviews Drug Discovery, 16, 457–471.

    Article  CAS  PubMed  Google Scholar 

  • Durrant, J. D., & Amaro, R. E. (2015). Machine-learning techniques applied to antibacterial drug discovery. Chemical Biology & Drug Design, 85, 14–21.

    Article  CAS  Google Scholar 

  • Fernandes, P., & Martens, E. (2017). Antibiotics in late clinical development. Biochemical Pharmacology, 133, 152–163.

    Article  CAS  PubMed  Google Scholar 

  • Flamm, R. K., Farrell, D. J., Rhomberg, P. R., Scangarella-Oman, N. E., & Sader, H. S. (2017). Gepotidacin (GSK2140944) in vitro activity against Gram-positive and Gram-negative bacteria. Antimicrobial Agents and Chemotherapy, 61, pii: e00468-17. https://doi.org/10.1128/AAC.00468-17.

    Article  Google Scholar 

  • Francisco, R., Fields, F. R., Lee, S. W., & McConnell, M. J. (2017). Using bacterial genomes and essential genes for the development of new antibiotics. Biochemical Pharmacology, 134, 74–86.

    Article  CAS  Google Scholar 

  • Galkina, C. E., Beierlein, J. M., Khanuja, N. S., McNamee, L. M., & Ledley, F. D. (2018). Contribution of NIH funding to new drug approvals 2010-2016. Proceedings of the National Academy of Sciences of the United States of America, 115(10), 2329–2334.

    Article  CAS  Google Scholar 

  • Gwynn, M. N., Portnoy, A., Rittenhouse, S. F., & Payne, D. J. (2010). Challenges of antibacterial discovery revisited. Annals of the New York Academy of Sciences, 1213, 5–19.

    Article  PubMed  Google Scholar 

  • Hoffman, P. S., Sission, G., Croxen, M. A., Welch, K., Harman, W. D., Cremades, N., & Morash, M. G. (2007). Antiparasitic drug nitazoxanide inhibits the pyruvate oxidoreductases of Helicobacter pylori and selected anaerobic bacteria and parasites, and Campylobacter jejuni. Antimicrobial Agents and Chemotherapy, 51, 868–876.

    Article  CAS  PubMed  Google Scholar 

  • Hoffman, P. S., Bruce, A. M., Olekhnovich, I., Warren, C. A., Burgess, S. L., Hontecillas, R., Viladomiu, M., Bassaganya-Riera, J., Guerrant, R. L., & Macdonald, T. L. (2014). Preclinical studies of amixicile: A systemic therapeutic developed for treatment of Clostridium difficile infections also shows efficacy against Helicobacter pylori. Antimicrobial Agents and Chemotherapy, 58, 4703–4712.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Horner, D. S., Hirt, R. P., & Embley, T. M. (1999). A single eubacterial origin of eukaryotic pyruvate:ferredoxin oxidoreductase genes: Implications for the evolution of anaerobic eukaryotes. Molecular Biology and Evolution, 16, 1280–1291.

    Article  CAS  PubMed  Google Scholar 

  • Hutcherson, J. A., Sinclair, K. M., Belvin, B. R., Gui, Q., Hoffman, P. S., & Lewis, J. P. (2017). Amixicile, a novel strategy for targeting oral anaerobic pathogens. Scientific Reports, 7(1), 10474.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Iannini, P. B. (2002). Cardiotoxicity of macrolides, ketolides and fluoroquinolones that prolong the QTc interval. Expert Opinion on Drug Safety, 2002(1), 121–128.

    Article  Google Scholar 

  • Ibberson, C. B., Stacy, A., Fleming, D., Dees, J. L., Rumbaugh, K., Gilmore, M. S., & Whiteley, M. (2017). Co-infecting microorganisms dramatically alter pathogen gene essentiality during polymicrobial infection. Nature Microbiology, 2, 17079.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jackson, N., Czaplewski, L., & Piddock, L. J. V. (2018). Discovery and development of new antibacterial drugs: Learning from experience? Journal of Antimicrobial Chemotherapy. https://doi.org/10.1093/jac/dky019.

    Article  CAS  Google Scholar 

  • Kennedy, A. J., Bruce, A. M., Gineste, C., Ballard, T. E., Olekhnovich, I. N., Macdonald, T. L., & Hoffman, P. S. (2016). Synthesis and antimicrobial evaluation of amixicile-based inhibitors of the pyruvate-ferredoxin oxidoreductases of anaerobic bacteria and epsilonproteobacteria. Antimicrobial Agents and Chemotherapy, 60, 3980–3987.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lewis, K. (2013). Platforms for antibiotic discovery. Nature Reviews. Drug Discovery, 12, 371–387.

    Article  CAS  PubMed  Google Scholar 

  • Lewis, K. (2017). New approaches to antimicrobial discovery. Biochemical Pharmacology, 15(134), 87–98.

    Article  CAS  Google Scholar 

  • Ling, L. L., Schneider, T., Peoples, A. J., Spoering, A. L., Engels, I., Conlon, B. P., Mueller, A., Schäberle, T. F., Hughes, D. E., Epstein, S., Jones, M., Lazarides, L., Steadman, V. A., Cohen, D. R., Felix, C. R., Fetterman, K. A., Millett, W. P., Nitti, A. G., Zullo, A. M., Chen, C., & Lewis, K. (2015). A new antibiotic kills pathogens without detectable resistance. Nature, 517(7535), 455–459.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Mitsugi, R., Sumida, K., Fujie, Y., Tukey, R. H., Itoh, T., & Fujiwara, R. (2016). Acyl-glucuronide as a possible cause of trovafloxacin-induced liver toxicity: Induction of chemokine (C-X-C Motif) ligand 2 by trovafloxacin acyl-glucuronide. Biological & Pharmaceutical Bulletin, 39, 1604–1610.

    Article  CAS  Google Scholar 

  • Mitton-Fry, M. J., Brickner, S. J., Hamel, J. C., Barham, R., Brennan, L., Casavant, J. M., Ding, X., Finegan, S., Hardink, J., Hoang, T., Huband, M. D., Maloney, M., Marfat, A., McCurdy, S. P., McLeod, D., Subramanyam, C., Plotkin, M., Reilly, U., Schafer, J., Stone, G. G., Uccello, D. P., Wisialowski, T., Yoon, K., Zaniewski, R., & Zook, C. (2017). Novel 3-fluoro-6-methoxyquinoline derivatives as inhibitors of bacterial DNA gyrase and topoisomerase IV. Bioorganic & Medicinal Chemistry Letters, 27, 3353–3358.

    Article  CAS  Google Scholar 

  • O’Dwyer, K., Spivak, A. T., Ingraham, K., Min, S., Holmes, D. J., Jakielaszek, C., Rittenhouse, S., Kwan, A. L., Livi, G. P., Sathe, G., Thomas, E., Van Horn, S., Miller, L. A., Twynholm, M., Tomayko, J., Dalessandro, M., Caltabiano, M., Scangarella-Oman, N. E., & Brown, J. R. (2015). Bacterial resistance to leucyl-tRNA synthetase inhibitor GSK2251052 develops during treatment of complicated urinary tract infections. Antimicrobial Agents and Chemotherapy, 59, 289–298.

    Article  PubMed  CAS  Google Scholar 

  • Page, M. G., & Bush, K. (2014). Discovery and development of new antibacterial agents targeting Gram-negative bacteria in the era of pandrug resistance: Is the future promising? Current Opinion in Pharmacology, 18, 91–97.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Payne, D. J., Miller, L. F., Findlay, D., Anderson, J., & Marks, L. (2015). Time for a change: Addressing R&D and commercialization challenges for antibacterials. Philosophical Transactions of the Royal Society B, 370, 2014086.

    Article  Google Scholar 

  • Qu, Y., Olsen, J. R., Yuan, X., Cheng, P. F., Levesque, M. P., Brokstad, K. A., Hoffman, P. S., Oyan, A. M., Zhang, W., Kalland, K. H., & Ke, X. (2018). Small molecule promotes β-catenin citrullination and inhibits Wnt signaling in cancer. Nature Chemical Biology, 14, 94–101.

    Article  CAS  PubMed  Google Scholar 

  • Richter, M. F., Hergenrother, P. J. (2018). The challenge of converting gram-positive-only compounds into broad-spectrum antibiotics. Annals of the New York Academy of Sciences February 15. https://doi.org/10.1111/nyas.13598.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Richter, M. F., Drown, B. S., Riley, A. P., Garcia, A., Shirai, T., Svec, R. L., & Hergenrother, P. J. (2017). Predictive compound accumulation rules yield a broad-spectrum antibiotic. Nature, 545(7654), 299–304.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rossignol, J. F. (2014). Nitazoxanide: A first-in-class broad-spectrum antiviral agent. Antiviral Research, 110, 94–103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Senkowski, W., Zhang, X., Olofsson, M. H., Isacson, R., Höglund, U., Gustafsson, M., Nygren, P., Linder, S., Larsson, R., & Fryknäs, M. (2015). Three-dimensional cell culture-based screening identifies the anthelmintic drug nitazoxanide as a candidate for treatment of colorectal cancer. Molecular Cancer Therapeutics, 14(6), 1504–1516.

    Article  CAS  PubMed  Google Scholar 

  • Shakya, A., Bhat, H. R., Ghosh, S. K. (2017). Update on nitazoxanide: A multifunctional chemotherapeutic agent. Current Drug Discovery Technologies July 27. https://doi.org/10.2174/1570163814666170727130003.

    Article  CAS  PubMed  Google Scholar 

  • Shamir, E. R., Warthan, M., Brown, S. P., Nataro, J. P., Guerrant, R. L., & Hoffman, P. S. (2010). Nitazoxanide inhibits biofilm production and hemagglutination by enteroaggregative Escherichia coli strains by blocking assembly of AafA fimbriae. Antimicrobial Agents and Chemotherapy, 54, 1526–1533.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Silver, L. (2011). Challenges of antibacterial discovery. Clinical Microbiology Reviews, 24, 71–109.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sisson, G., Jeong, J. Y., Goodwin, A., Bryden, L., Rossler, N., Lim-Morrison, S., Raudonikiene, A., Berg, D. E., & Hoffman, P. S. (2000). Metronidazole activation is mutagenic and causes DNA fragmentation in Helicobacter pylori and in Escherichia coli containing a cloned H. pylori RdxA(+) (Nitroreductase) gene. Journal of Bacteriology, 182(18), 5091–5096.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • So, A. D., Gupta, N., Brahmachari, S. K., et al. (2011). Towards a new business models for R&D for novel antibiotics. Drug Resistaence Updates, 14, 88–94.

    Article  CAS  Google Scholar 

  • Sun, J., Zhang, H., Liu, Y. H., & Feng, Y. (2018). Towards understanding MCR-like colistin resistance. Trends in Microbiology. Mar 7. pii: S0966-842X(18)30042-8.

    Google Scholar 

  • Tilmanis, D., van Baalen, C., Oh, D. Y., Rossignol, J. F., & Hurt, A. C. (2017). The susceptibility of circulating human influenza viruses to tizoxanide, the active metabolite of nitazoxanide. Antiviral Research, 147, 142–148.

    Article  CAS  PubMed  Google Scholar 

  • Van Bambeke, F. (2015). Lipoglycopeptide antibacterial agents in Gram-positive infections: A comparative review. Drugs, 75, 2073–2095.

    Article  PubMed  CAS  Google Scholar 

  • Warren, C. A., van Opstal, E., Ballard, T. E., Kennedy, A., Wang, X., Riggins, M., Olekhnovich, I., Warthan, M., Kolling, G. L., Guerrant, R. L., Macdonald, T. L., & Hoffman, P. S. (2012). Amixicile: A novel inhibitor of pyruvate: Ferredoxin oxidoreductase shows efficacy against Clostridium difficile in a mouse infection model. Antimicrobial Agents and Chemotherapy, 56, 1403–1411.

    Article  CAS  Google Scholar 

  • Wright, P. M., Seiple, I. B., & Myers, A. G. (2014). The evolving role of chemical synthesis in antibacterial drug discovery. Angewandte Chemie (International Ed. in English), 53(34), 8840–8869.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, VA, USA

    Paul S. Hoffman

Authors
  1. Paul S. Hoffman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Paul S. Hoffman .

Editor information

Editors and Affiliations

  1. Agricultural Microbiology, Faculty of Agricultural Sciences, Aligarh Muslim University, Aligarh, Uttar Pradesh, India

    Iqbal Ahmad

  2. Institute of Ophthalmology, JN Medical College, Aligarh Muslim University, Aligarh, Uttar Pradesh, India

    Shamim Ahmad

  3. School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA

    Kendra P. Rumbaugh

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Singapore Pte Ltd.

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Hoffman, P.S. (2019). Impediments to Discovery of New Antimicrobials with New Modes of Action. In: Ahmad, I., Ahmad, S., Rumbaugh, K. (eds) Antibacterial Drug Discovery to Combat MDR. Springer, Singapore. https://doi.org/10.1007/978-981-13-9871-1_7

Download citation

Publish with us

Policies and ethics

Search

Navigation