Abstract
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.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Abedon, S. T., GarcĂa, P., Mullany, P., & Aminov, R. (2017). Editorial: Phage therapy: Past, present and future. Frontiers in Microbiology, 8, 981. https://doi.org/10.3389/fmicb.2017.00981. PMCID: PMC5471325. PMID: 28663740.
Adenium Biotech Pipeline. http://adeniumbiotech.com/pipeline. Accessed 18 July 2018.
Amplifi Bioscience Corporation. https://www.ampliphibio.com/pipeline/ab-sa01/. Accessed 3 May 2019.
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.
Ardis Pharmaceuticals. http://ardispharma.com/aerucin/. Accessed 11 July 2018.
Ardis Pharmaceuticals. http://ardispharma.com/Ar-301. Accessed 11 July 2018.
Behring, E., & Kitasako, S. (1890). Ueber das Zustandekommen der Diphtherie-Immunitat und der Tetanus. Immunitatbei Thieren. Deutsche Medizinische Wochenschrift, 16, 1113–1114.
Bradshaw, J. (2003). Cationic antimicrobial peptides: Issues for potential clinical use. BioDrugs, 17, 233–240.
Brogden, K. A. (2005). Antimicrobial peptides: Pore formers or metabolic inhibitors in bacteria? Nature Reviews Microbiology, 3, 238–250.
Camilli, A., & Bassler, B. L. (2006). Bacterial small-molecule signaling pathways. Science, 311, 1113–1116.
Clark, I. A. (2007). The advent of the cytokine storm. Immunology and Cell Biology, 85, 271–273.
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.
De la Fuente-NĂºĂ±ez, C., Reffuveille, F., FernĂ¡ndez, 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.
De la Fuente-NĂºĂ±ez, 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.
de la Fuente-NĂºĂ±ez, 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.
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.
Fenton, M., Ross, P., & McAuliffe, O. (2010). Recombinant bacteriophage lysins as antibacterials. Bioengineered Bugs, 1(1), 9–16.
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.
Fox, J. L. (2013). Antimicrobial peptides stage a comeback. Nature Biotechnology, 31, 379–382.
Greig, S. L. (2016). Obiltoxaximab: First global approval. Drugs, 76(7), 823–830.
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.
Hamill, P., Brown, K., Jenssen, H., et al. (2008). Novel anti-infectives: Is host defence the answer? Current Opinion in Biotechnology, 19, 628–636.
Hancock, R. E., & Sahl, H. G. (2006). Antimicrobial and host-defense peptides as new anti-infective therapeutic strategies. Nature Biotechnology, 24, 1551–1557.
Hancock, R. E., Nijnik, A., & Philpott, D. J. (2012). Modulating immunity as a therapy for bacterial infections. Nature Reviews. Microbiology, 10(4), 243.
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.
A Study to Evaluate the Safety, Pharmacokinetics and Pharmacodynamics of N-Rephasin® SAL200 in Healthy Male Volunteers. https://clinicaltrials.gov/ct2/show/NCT01855048. Accessed 14 Aug 2018.
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.
Karin, M., Lawrence, T., & Nizet, V. (2006). Innate immunity gone awry: Linking microbial infections to chronic inflammation and cancer. Cell, 124, 823–835.
Koczulla, A. R., & Bals, R. (2003). Antimicrobial peptides: Current status and therapeutic potential. Drugs, 63, 389–406.
Kosikowska, P., & Lesner, A. (2016). Antimicrobial peptides (AMPs) as drug candidates: A patent review (2003-2015). Expert Opinion on Therapeutic Patents, 26, 689–702.
Landman, D., Georgescu, C., Martin, D. A., et al. (2008). Polymyxins revisited. Clinical Microbiology Reviews, 21, 449–465.
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.
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.
Mansour, S. C., de la Fuente-NĂºĂ±ez, 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.
Markham, A. (2016). Bezlotoxumab: First global approval. Drugs, 76(18), 1793–1798.
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.
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.
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.
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.
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.
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.
Novacta Biosystems NVB302. http://www.novactabio.com/careers.php. Accessed 14 Aug 2018.
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.
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.
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.
Pletzer, D., & Hancock, R. E. (2016). Antibiofilm peptides: Potential as broad-spectrum agents. Journal of Bacteriology, 198(19), 2572–2578.
Murepavadin POL7080. http://www.polyphor.com/products/pol7080. Accessed 14 Aug 2018.
Quan-Guo, Z., & Buckling, A. (2012). Phages limit the evolution of bacterial antibiotic resistance in experimental microcosms. Evolutionary Applications, 5(6), 575–582.
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.
Reffuveille, F., de la Fuente-NĂºĂ±ez, 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.
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. https://doi.org/10.1016/j.ijantimicag.2011.08.009. Epub 2011 Oct 5.
Round, J. L., & Mazmanian, S. K. (2009). The gut microbiota shapes intestinal immune responses during health and disease. Nature Reviews Immunology, 9, 313–323.
Scherer, A., & McLean, A. (2002). Mathematical models of vaccination. British Medical Bulletin, 62, 187–199.
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.
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.
Schrezenmeir, J., & de Vrese, M. (2001). Probiotics, prebiotics, and synbiotics—Approaching a definition. The American Journal of Clinical Nutrition, 73(2), 361S–364S.
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.
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.
Senok, A. C., Verstraelen, H., Temmerman, M., et al. (2009). Probiotics for the treatment of bacterial vaginosis. Cochrane Database of Systematic Reviews, 4, CD006289.
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.
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.
Sorbara, M., & Philpott, D. (2011). Peptidoglycan: A critical activator of the mammalian immune system during infection and homeostasis. Immunological Reviews, 243, 40–60.
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.
Sutherland, I. W. (2001). The biofilm matrix—An immobilized but dynamic microbial environment. Trends in Microbiology, 9, 222–227.
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.
Trinchieri, G., & Sher, A. (2007). Cooperation of Toll-like receptor signals in innate immune defence. Nature Reviews Immunology, 7, 179–190.
Twetman, S., & Stecksen-Blicks, C. (2008). Probiotics and oral health effects in children. International Journal of Paediatric Dentistry, 18, 3–10.
Ulevitch, R. J. (2004). Therapeutics targeting the innate immune system. Nature Reviews Immunology, 4, 512–520.
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.
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.
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.
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.
Wright, A., Shin, S. U., & Morrison, S. L. (1992). Genetically engineered antibodies: Progress and prospects. Critical Reviews in Immunology, 12(3–4), 125–126.
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.
About Cystic Fibrosis CF Foundation. https://www.cff.org/What-is-CF/About-Cystic-Fibrosis/. Accessed 14 Aug 2018.
Yeaman, M. R., & Yount, N. Y. (2003). Mechanisms of antimicrobial peptide action and resistance. Pharmacological Reviews, 55, 27–55.
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. https://doi.org/10.1128/AAC.01020-16.
Zasloff, M. (2002). Antimicrobial peptides of multicellular organisms. Nature, 415, 389–395.
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.
Acknowledgements
This manuscript bears CSIR-CDRI communication number 9730.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2019 Springer Nature Singapore Pte Ltd.
About this chapter
Cite this chapter
Kaul, G., Shukla, M., Dasgupta, A., Chopra, S. (2019). Alternative Therapies to Antibiotics to Combat Drug-Resistant Bacterial Pathogens. 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_9
Download citation
DOI: https://doi.org/10.1007/978-981-13-9871-1_9
Published:
Publisher Name: Springer, Singapore
Print ISBN: 978-981-13-9870-4
Online ISBN: 978-981-13-9871-1
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)