Alternative Therapies to Antibiotics to Combat Drug-Resistant Bacterial Pathogens

  • Grace Kaul
  • Manjulika Shukla
  • Arunava Dasgupta
  • Sidharth Chopra


The unabated emergence and spread of antimicrobial resistance (AMR) within both nosocomial and community environments is the driving force behind the urgent need to discover novel antimicrobial agents. However, owing to the challenges faced during conventional drug discovery programmes and the concomitant paucity of new drugs, it is prudent to focus on non-conventional approaches that could serve as alternatives to antibiotics. These approaches include all non-compound approaches that target pathogens other than antibiotics. Although these alternatives may or may not be absolute replacements of antibiotics, they can certainly be used in prophylaxis and in combination therapies with antibiotics to reduce the overuse and help prevent AMR. The advantage of this approach includes specific inhibition of pathogens without effecting the host’s commensal beneficial microbiome. This is in direct contrast to antibiotic therapies which disturb the commensal bacteria, leading to increased risks of Clostridium difficile-associated diarrhoea, vaginal Candida albicans infections and the exacerbation of asthma and allergic diseases. Although a consistent efficacy is lacking, switching to alternatives will certainly reduce antibiotic abuse to a large extent and consequent resistance. Further development of these specific approaches is warranted to improve deliverability, potency and reliability. Thus, the investigation of novel non-antibiotic approaches for the prevention of, and protection against, infectious diseases should be stimulated, and such approaches must be high-priority research and development projects. The alternative approaches to antibiotics include immunomodulation, competitive exclusion of pathogenic bacteria via probiotics and their combination, natural and synthetic antimicrobial peptides, antibodies, bacteriophages and phage lysins. These alternative strategies are considered in this chapter.


Antimicrobial resistance (AMR) Immunomodulins Antimicrobial peptides Probiotics Antibodies Bacteriophages Lysins 



This manuscript bears CSIR-CDRI communication number 9730.


  1. Abedon, S. T., García, P., Mullany, P., & Aminov, R. (2017). Editorial: Phage therapy: Past, present and future. Frontiers in Microbiology, 8, 981. PMCID: PMC5471325. PMID: 28663740.
  2. Adenium Biotech Pipeline. Accessed 18 July 2018.
  3. Amplifi Bioscience Corporation. Accessed 3 May 2019.
  4. Antonelli, L. R., Rothfuchs, A. G., Gonçalves, R., et al. (2010). Intranasal Poly-IC treatment exacerbates tuberculosis in mice through the pulmonary recruitment of a pathogen-permissive monocyte/macrophage population. The Journal of Clinical Investigation, 120(5), 1674–1682.PubMedPubMedCentralCrossRefGoogle Scholar
  5. Ardis Pharmaceuticals. Accessed 11 July 2018.
  6. Ardis Pharmaceuticals. Accessed 11 July 2018.
  7. Behring, E., & Kitasako, S. (1890). Ueber das Zustandekommen der Diphtherie-Immunitat und der Tetanus. Immunitatbei Thieren. Deutsche Medizinische Wochenschrift, 16, 1113–1114.CrossRefGoogle Scholar
  8. Bradshaw, J. (2003). Cationic antimicrobial peptides: Issues for potential clinical use. BioDrugs, 17, 233–240.PubMedCrossRefPubMedCentralGoogle Scholar
  9. Brogden, K. A. (2005). Antimicrobial peptides: Pore formers or metabolic inhibitors in bacteria? Nature Reviews Microbiology, 3, 238–250.PubMedCrossRefPubMedCentralGoogle Scholar
  10. Camilli, A., & Bassler, B. L. (2006). Bacterial small-molecule signaling pathways. Science, 311, 1113–1116.PubMedPubMedCentralCrossRefGoogle Scholar
  11. Clark, I. A. (2007). The advent of the cytokine storm. Immunology and Cell Biology, 85, 271–273.PubMedCrossRefPubMedCentralGoogle Scholar
  12. Cosseau, C., Devine, D. A., Dullaghan, E., et al. (2008). The commensal Streptococcus salivarius K12 downregulates the innate immune responses of human epithelial cells and promotes host-microbe homeostasis. Infection and Immunity, 76, 4163–4175.PubMedPubMedCentralCrossRefGoogle Scholar
  13. De la Fuente-Núñez, C., Reffuveille, F., Fernández, L., & Hancock, R. E. (2013). Bacterial biofilm development as a multicellular adaptation: Antibiotic resistance and new therapeutic strategies. Current Opinion in Microbiology, 16(5), 580–589.PubMedCrossRefPubMedCentralGoogle Scholar
  14. De la Fuente-Núñez, C., Reffuveille, F., Haney, E. F., et al. (2014). Broad-spectrum anti-biofilm peptide that targets a cellular stress response. PLoS Pathogens, 10(5), e1004152.PubMedPubMedCentralCrossRefGoogle Scholar
  15. de la Fuente-Núñez, C., Reffuveille, F., Mansour, S. C., et al. (2015). Denantiomeric peptides that eradicate wild-type and multidrug-resistant biofilms and protect against lethal Pseudomonas aeruginosa infections. Chemistry & Biology, 22, 196–205.CrossRefGoogle Scholar
  16. Falagas, M. E., & Kasiakou, S. K. (2006). Toxicity of polymyxins: A systematic review of the evidence from old and recent studies. Critical Care, 10(1), R27.PubMedPubMedCentralCrossRefGoogle Scholar
  17. Fenton, M., Ross, P., & McAuliffe, O. (2010). Recombinant bacteriophage lysins as antibacterials. Bioengineered Bugs, 1(1), 9–16.PubMedPubMedCentralCrossRefGoogle Scholar
  18. Fjell, C. D., Hiss, J. A., Hancock, R. E. W., et al. (2011). Designing antimicrobial peptides: Form follows function. Nature Reviews Drug Discovery, 11, 37–51.PubMedCrossRefPubMedCentralGoogle Scholar
  19. Fox, J. L. (2013). Antimicrobial peptides stage a comeback. Nature Biotechnology, 31, 379–382.PubMedCrossRefPubMedCentralGoogle Scholar
  20. Greig, S. L. (2016). Obiltoxaximab: First global approval. Drugs, 76(7), 823–830.PubMedCrossRefPubMedCentralGoogle Scholar
  21. Hafez, M., Hayes, K., Goldrick, M., et al. (2009). The K5 capsule of Escherichia coli strain Nissle 1917 is important in mediating interactions with intestinal epithelial cells and chemokine induction. Infection and Immunity, 77, 2995–3003.PubMedPubMedCentralCrossRefGoogle Scholar
  22. Hamill, P., Brown, K., Jenssen, H., et al. (2008). Novel anti-infectives: Is host defence the answer? Current Opinion in Biotechnology, 19, 628–636.PubMedCrossRefPubMedCentralGoogle Scholar
  23. Hancock, R. E., & Sahl, H. G. (2006). Antimicrobial and host-defense peptides as new anti-infective therapeutic strategies. Nature Biotechnology, 24, 1551–1557.PubMedCrossRefPubMedCentralGoogle Scholar
  24. Hancock, R. E., Nijnik, A., & Philpott, D. J. (2012). Modulating immunity as a therapy for bacterial infections. Nature Reviews. Microbiology, 10(4), 243.PubMedCrossRefPubMedCentralGoogle Scholar
  25. Huynh, T., Stecher, M., McKinnon, J., et al. (2016). Safety and tolerability of 514G3, a true human anti-protein A monoclonal antibody for the treatment of S. aureus bacteremia. Open Forum Infectious Diseases, 3(1), 1354.CrossRefGoogle Scholar
  26. A Study to Evaluate the Safety, Pharmacokinetics and Pharmacodynamics of N-Rephasin® SAL200 in Healthy Male Volunteers. Accessed 14 Aug 2018.
  27. Karaolis, D. K., Cheng, K., Lipsky, M., et al. (2005). 3′,5ʹ-cyclic diguanylic acid (c-di-GMP) inhibits basal and growth factor-stimulated human colon cancer cell proliferation. Biochemical and Biophysical Research Communications, 329, 40–45.PubMedCrossRefPubMedCentralGoogle Scholar
  28. Karin, M., Lawrence, T., & Nizet, V. (2006). Innate immunity gone awry: Linking microbial infections to chronic inflammation and cancer. Cell, 124, 823–835.PubMedCrossRefPubMedCentralGoogle Scholar
  29. Koczulla, A. R., & Bals, R. (2003). Antimicrobial peptides: Current status and therapeutic potential. Drugs, 63, 389–406.PubMedCrossRefGoogle Scholar
  30. Kosikowska, P., & Lesner, A. (2016). Antimicrobial peptides (AMPs) as drug candidates: A patent review (2003-2015). Expert Opinion on Therapeutic Patents, 26, 689–702.PubMedCrossRefPubMedCentralGoogle Scholar
  31. Landman, D., Georgescu, C., Martin, D. A., et al. (2008). Polymyxins revisited. Clinical Microbiology Reviews, 21, 449–465.PubMedPubMedCentralCrossRefGoogle Scholar
  32. Lebeer, S., Vanderleyden, J., & De Keersmaecker, S. C. (2010). Host interactions of probiotic bacterial surface molecules: Comparison with commensals and pathogens. Nature Reviews Microbiology, 8, 171–184.PubMedCrossRefPubMedCentralGoogle Scholar
  33. Liu, P. T., Stenger, S., Li, H., et al. (2006). Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science, 311, 1770–1773.PubMedCrossRefPubMedCentralGoogle Scholar
  34. Mansour, S. C., de la Fuente-Núñez, C., & Hancock, R. E. W. (2015). Peptide IDR-1018: Modulating the immune system and targeting bacterial biofilms to treat antibiotic-resistant bacterial infections. Journal of Peptide Science, 21, 323–329.PubMedCrossRefPubMedCentralGoogle Scholar
  35. Markham, A. (2016). Bezlotoxumab: First global approval. Drugs, 76(18), 1793–1798.PubMedCrossRefPubMedCentralGoogle Scholar
  36. Bitzan, M., Poole, R., Mehran, M., et al. (2009). Safety and pharmacokinetics of chimeric anti-shiga toxin 1 and anti-shiga toxin 2 monoclonal antibodies in healthy volunteers. Antimicrobial Agents and Chemotherapy, 53(7), 3081–3087.PubMedPubMedCentralCrossRefGoogle Scholar
  37. Martineau, A. R., Timms, P. M., Bothamley, G. H., et al. (2011). High-dose vitamin D3 during intensive-phase antimicrobial treatment of pulmonary tuberculosis: A double-blind randomised controlled trial. Lancet, 377, 242–250.PubMedPubMedCentralCrossRefGoogle Scholar
  38. Mattmann, M. E., & Blackwell, H. E. (2010). Small molecules that modulate quorum sensing and control virulence in Pseudomonas aeruginosa. The Journal of Organic Chemistry, 75, 6737–6746.PubMedPubMedCentralCrossRefGoogle Scholar
  39. Mayer, M. L., Easton, D. M., & Hancock, R. E. W. (2010). Fine tuning host responses in the face of infection: Emerging roles and clinical applications of host defence peptides. In G. Wang (Ed.), Antimicrobial peptides: Discovery, design and novel therapeutic strategies (18th ed., pp. 195–220). Cambridge, MA: CABI.CrossRefGoogle Scholar
  40. Migone, T. S., Subramanian, G. M., Zhong, J., et al. (2009). Raxibacumab for the treatment of inhalational anthrax. The New England Journal of Medicine, 361(2), 135–144.PubMedCrossRefPubMedCentralGoogle Scholar
  41. Miyairi, S., Tateda, K., Fuse, E. T., et al. (2006). Immunization with 3-oxododecanoyl-l-homoserine lactone-protein conjugate protects mice from lethal Pseudomonas aeruginosa lung infection. Journal of Medical Microbiology, 55, 1381–1387.PubMedCrossRefPubMedCentralGoogle Scholar
  42. Novacta Biosystems NVB302. Accessed 14 Aug 2018.
  43. Opal, S. M., Laterre, P. F., Francois, B., et al. (2013). ACCESS Study Group. Effect of eritoran, an antagonist of MD2-TLR4, on mortality in patients with severe sepsis: The ACCESS randomized trial. JAMA, 309(11), 1154–1162.PubMedCrossRefPubMedCentralGoogle Scholar
  44. Overhage, J., Campisano, A., Bains, M., et al. (2008). Human host defense peptide LL-37 prevents bacterial biofilm formation. Infection and Immunity, 76, 4176–4182.PubMedPubMedCentralCrossRefGoogle Scholar
  45. Pabary, R., Singh, C., & Morales, S. (2015). Anti-Pseudomonal bacteriophage reduces infective burden and inflammatory response in murine lung. Antimicrobial Agents and Chemotherapy, 60(2), 744–751.PubMedCrossRefPubMedCentralGoogle Scholar
  46. Pletzer, D., & Hancock, R. E. (2016). Antibiofilm peptides: Potential as broad-spectrum agents. Journal of Bacteriology, 198(19), 2572–2578.PubMedPubMedCentralCrossRefGoogle Scholar
  47. Murepavadin POL7080. Accessed 14 Aug 2018.
  48. Quan-Guo, Z., & Buckling, A. (2012). Phages limit the evolution of bacterial antibiotic resistance in experimental microcosms. Evolutionary Applications, 5(6), 575–582.CrossRefGoogle Scholar
  49. Raqib, R., Sarker, P., Bergman, P., et al. (2006). Improved outcome in shigellosis associated with butyrate induction of an endogenous peptide antibiotic. Proceedings of the National Academy of Sciences of the United States of America, 103, 9178–9183.PubMedPubMedCentralCrossRefGoogle Scholar
  50. Reffuveille, F., de la Fuente-Núñez, C., Mansour, S., & Hancock, R. E. (2014). A broad-spectrum antibiofilm peptide enhances antibiotic action against bacterial biofilms. Antimicrobial Agents and Chemotherapy, 58(9), 5363–5371.PubMedPubMedCentralCrossRefGoogle Scholar
  51. Resch, G., Moreillon, P., & Fischetti, V. A. (2011). A stable phage lysin (Cpl-1) dimer with increased antipneumococcal activity and decreased plasma clearance. International Journal of Antimicrobial Agents, 38(6), 516–521. Epub 2011 Oct 5.PubMedCrossRefPubMedCentralGoogle Scholar
  52. Round, J. L., & Mazmanian, S. K. (2009). The gut microbiota shapes intestinal immune responses during health and disease. Nature Reviews Immunology, 9, 313–323.PubMedPubMedCentralCrossRefGoogle Scholar
  53. Scherer, A., & McLean, A. (2002). Mathematical models of vaccination. British Medical Bulletin, 62, 187–199.PubMedCrossRefPubMedCentralGoogle Scholar
  54. Schlee, M., Wehkamp, J., Altenhoefer, A., et al. (2007). Induction of human beta-defensin 2 by the probiotic Escherichia coli Nissle 1917 is mediated through flagellin. Infection and Immunity, 75, 2399–2407.PubMedPubMedCentralCrossRefGoogle Scholar
  55. Schlee, M., Harder, J., Köten, B., et al. (2008). Probiotic lactobacilli and VSL#3 induce enterocyte beta-defensin 2. Clinical and Experimental Immunology, 151(3), 528–535.PubMedPubMedCentralCrossRefGoogle Scholar
  56. Schrezenmeir, J., & de Vrese, M. (2001). Probiotics, prebiotics, and synbiotics—Approaching a definition. The American Journal of Clinical Nutrition, 73(2), 361S–364S.PubMedCrossRefPubMedCentralGoogle Scholar
  57. Scott, M. G., Dullaghan, E., Mookherjee, N., et al. (2007). An anti-infective peptide that selectively modulates the innate immune response. Nature Biotechnology, 25, 465–472.PubMedCrossRefPubMedCentralGoogle Scholar
  58. Secher, T., Fas, S., Fauconnier, L., et al. (2013). The anti-Pseudomonas aeruginosa antibody panobacumab is efficacious on acute pneumonia in neutropenic mice and has additive effects with meropenem. PLoS One, 8(9), e73396.PubMedPubMedCentralCrossRefGoogle Scholar
  59. Senok, A. C., Verstraelen, H., Temmerman, M., et al. (2009). Probiotics for the treatment of bacterial vaginosis. Cochrane Database of Systematic Reviews, 4, CD006289.Google Scholar
  60. Smith, R. S., Harris, S. G., Phipps, R., et al. (2002). The Pseudomonas aeruginosa quorum-sensing molecule N-(3-oxododecanoyl)homoserine lactone contributes to virulence and induces inflammation in vivo. Journal of Bacteriology, 184, 1132–1139.PubMedPubMedCentralCrossRefGoogle Scholar
  61. Smyth, A. R., Cifelli, P. M., Ortori, C. A., et al. (2010). Garlic as an inhibitor of Pseudomonas aeruginosa quorum sensing in cystic fibrosis—A pilot randomized controlled trial. Pediatric Pulmonology, 45, 6–362.Google Scholar
  62. Sorbara, M., & Philpott, D. (2011). Peptidoglycan: A critical activator of the mammalian immune system during infection and homeostasis. Immunological Reviews, 243, 40–60.PubMedCrossRefPubMedCentralGoogle Scholar
  63. Spreafico, R., Ricciardi-Castagnoli, P., & Mortellaro, A. (2010). The controversial relationship between NLRP3, alum, danger signals and the next-generation adjuvants. European Journal of Immunology, 40, 638–642.PubMedCrossRefPubMedCentralGoogle Scholar
  64. Sutherland, I. W. (2001). The biofilm matrix—An immobilized but dynamic microbial environment. Trends in Microbiology, 9, 222–227.PubMedCrossRefPubMedCentralGoogle Scholar
  65. Tidswell, M., et al. (2010). Phase 2 trial of eritoran tetrasodium (E5564), a Toll-like receptor 4 antagonist, in patients with severe sepsis. Critical Care Medicine, 38, 72–83.PubMedCrossRefPubMedCentralGoogle Scholar
  66. Trinchieri, G., & Sher, A. (2007). Cooperation of Toll-like receptor signals in innate immune defence. Nature Reviews Immunology, 7, 179–190.PubMedCrossRefPubMedCentralGoogle Scholar
  67. Twetman, S., & Stecksen-Blicks, C. (2008). Probiotics and oral health effects in children. International Journal of Paediatric Dentistry, 18, 3–10.PubMedPubMedCentralGoogle Scholar
  68. Ulevitch, R. J. (2004). Therapeutics targeting the innate immune system. Nature Reviews Immunology, 4, 512–520.PubMedCrossRefPubMedCentralGoogle Scholar
  69. Velden, W. J., van Iersel, T. M., Blijlevens, N. M., et al. (2009). Safety and tolerability of the antimicrobial peptide human lactoferrin 1-11 (hLF1-11). BMC Medicine, 7, 44.PubMedPubMedCentralCrossRefGoogle Scholar
  70. Warrener, P., Varkey, R., Bonnell, J. C., et al. (2014). A novel anti-PcrV antibody providing enhanced protection against Pseudomonas aeruginosa in multiple animal infection models. Antimicrobial Agents and Chemotherapy, 58(8), 4384–4391.PubMedPubMedCentralCrossRefGoogle Scholar
  71. Werts, C., Rubino, S., Ling, A., et al. (2011). Nod-like receptors in intestinal homeostasis, inflammation, and cancer. Journal of Leukocyte Biology, 90, 471–482.PubMedCrossRefPubMedCentralGoogle Scholar
  72. Willing, B. P., Russell, S. L., & Finlay, B. B. (2011). Shifting the balance: Antibiotic effects on host–microbiota mutualism. Nature Reviews Microbiology, 9, 233–243.PubMedCrossRefPubMedCentralGoogle Scholar
  73. Wright, A., Shin, S. U., & Morrison, S. L. (1992). Genetically engineered antibodies: Progress and prospects. Critical Reviews in Immunology, 12(3–4), 125–126.PubMedPubMedCentralGoogle Scholar
  74. Wu, H., Song, Z., Hentzer, M., et al. (2004). Synthetic furanones inhibit quorum-sensing and enhance bacterial clearance in Pseudomonas aeruginosa lung infection in mice. The Journal of Antimicrobial Chemotherapy, 53, 1054–1061.PubMedCrossRefPubMedCentralGoogle Scholar
  75. About Cystic Fibrosis CF Foundation. Accessed 14 Aug 2018.
  76. Yeaman, M. R., & Yount, N. Y. (2003). Mechanisms of antimicrobial peptide action and resistance. Pharmacological Reviews, 55, 27–55.PubMedCrossRefPubMedCentralGoogle Scholar
  77. Yu, X.-Q., Robbie, G. J., Wu, Y., et al. (2016). Safety, tolerability, and pharmacokinetics of MEDI4893, an investigational, extended-half-life, anti-Staphylococcus aureus alpha-toxin human monoclonal antibody, in healthy adults. Antimicrobial Agents and Chemotherapy, 61(1), e01020-16. Scholar
  78. Zasloff, M. (2002). Antimicrobial peptides of multicellular organisms. Nature, 415, 389–395.PubMedCrossRefGoogle Scholar
  79. Zavascki, A. P., Goldani, L. Z., Li, J., et al. (2007). Polymyxin B for the treatment of multidrug-resistant pathogens: A critical review. The Journal of Antimicrobial Chemotherapy, 60, 1206–1215.PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  • Grace Kaul
    • 1
  • Manjulika Shukla
    • 1
  • Arunava Dasgupta
    • 1
  • Sidharth Chopra
    • 1
  1. 1.Division of MicrobiologyCSIR-Central Drug Research InstituteLucknowIndia

Personalised recommendations