The road towards the research and development of alternatives to antibiotics

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1 The road towards the research and development of alternatives to antibiotics Cyril G. Gay, DVM, Ph.D Senior National Program Leader Animal Production and Protection

2 Topics to be discussed Introduction Alternatives to antibiotics Antibiotic alternatives for growth promotion Next steps Conclusions

3 Topics to be discussed Introduction Alternatives to antibiotics Antibiotic alternatives for growth promotion Next steps Conclusions

4 Antimicrobial Resistance Alexander Fleming Penicillin Nobel Lecture, December 11, 1945 But I would like to sound one note of warning. Penicillin is to all intents and purposes non-poisonous so there is no need to worry about giving an overdose and poisoning the patient. There may be an danger, though, in under dosage. It is not difficult to make microbes resistant to penicillin in the laboratory exposing them to concentrations not sufficient to kill them, and the same thing has occasionally happened in the body..

6 Antibiotic Use in Food Animals Therapeutic - treatment of diseased animal Prophylactic - disease prevention Metaphylactic prophylactic/therapeutic use Growth promotion accelerate growth of animals Regardless of personal opinions: Increasing concern with antibiotic resistance Increased regulation restrict some antibiotics Examination of alternatives to conventional antibiotics is warranted

7 Topics to be discussed Introduction Alternatives to antibiotics Antibiotic alternatives for growth promotion Next steps Conclusions

8 Recommendations 13. To support relevant research to improve the understanding of the efficacy of current antimicrobial agents with the aim to prolong their usage while minimising the development of resistance, to develop new molecules and to find alternatives that could be used in animal production for antimicrobial agent substitutions.

10 What are alternatives to antibiotics? Alternatives to antibiotics are broadly defined as any substance that can be substituted for drugs that are increasingly becoming ineffective against pathogenic bacteria, viruses or parasites. Gay C.G., Seal B.S., Lillehoj H.S., Donovan D.M. (2014) Alternatives to Antibiotics: Recent Scientific Advancements. OIE Conference Booklet, Ed. 2014: Responsible and Prudent Use of Antimicrobial Agents for Animals;

12 Symposium Objectives 1) Highlight promising research results on alternatives to antibiotics, 2) Assess challenges associated with their commercialization and use, and 3) Provide actionable strategies to enable the development of alternatives.

13 Symposium Conclusions 1) Insufficient research to support their effective use in animal agriculture 2) Alternatives to antibiotics must be developed according to national and international standards and meet requirements for efficacy, safety, and quality 3) Regulatory pathways to enable the registration of alternatives to antibiotics are in place

15 Examples of alternatives to antibiotics Drugs, biologics, and feed additives Vaccines Microbial-derived Phytochemicals Immune-related Innovative drugs

16 Examples of alternatives to antibiotics Drugs, biologics, and feed additives Vaccines Microbial-derived Phytochemicals Immune-related Innovative drugs

Direct-Fed Microbials and Their Impact on the Intestinal Microflora and Immune System of Chickens: J.

17 Probiotics as Antibiotic Alternative to Improve Gut Health Cliniciansbrief.com Lee, K.W., H. Lillehoj, and Siragusa, G Direct-Fed Microbials and Their Impact on the Intestinal Microflora and Immune System of Chickens: J. Poultry Science. 47: Grant A, Gay CG, Lillehoj HS Bacillus spp. as direct-fed microbial antibiotic alternatives to enhance growth, immunity, and gut health in poultry. Avian Pathology 47: Thegutinstitute.com

18 Novel Gene-Editing Tools Using CRISPR - Cas 9 and Engineered Bacteriophages Ayhan DH, Tamer YT, Akbar M, Bailey SM, Wong M, Daly SM, et al. (2016) PLoS Biol 14(9)

19 Examples of alternatives to antibiotics Drugs, biologics, and feed additives Vaccines Microbial-derived therapeutics Phytochemicals Immune-related products Innovative drugs

20 Phytochemicals Plant Extracts

23 From black box to bold science Wlodarska, M. et al., Sci. Rep. 2015:5:9253. Kim et al., PLoS One 6:e27712 Kim, J, Lillehoj, H Res. Vet Sci. 102:

24 Examples of alternatives to antibiotics Drugs, biologics, and feed additives Vaccines Microbial-derived Phytochemicals Immune-related Innovative drugs, chemicals, and enzymes

Egg yolk IgY Antibodies as Antibiotic Alternative Large quantities of antibodies can be produced Collection of eggs is non-invasive Environmental friendly No risk of resistance No toxic residues

25 Egg yolk IgY Antibodies as Antibiotic Alternative Large quantities of antibodies can be produced Collection of eggs is non-invasive Environmental friendly No risk of resistance No toxic residues Homogenized and frozen Lee, SH., Lillehoj, HS. Et al., 2009 veterinary parasitology Gadde, U., Lillehoj, H., et al., Passive immunization with hyperim,mune egg yolk IgY as prophylaxis and therapy for poultry diseases- A Review. Animal Health Res Rev 16:

26 Antimicrobial Peptides: NK lysin kills all Apicomplexa

27 Topics to be discussed Introduction Alternatives to antibiotics Antibiotic alternatives for growth promotion Next steps Conclusions

28 Antibiotics and their alternatives Allen HK, et al.trends in Microbiology March 2013, Vol. 21, No. 3

Furness, J. B. et al. Nat. Rev. Gastroenterol.

10, 729 740 (2013) Nutrients Pathogens Metabolites

Functional Redundancy- Induced Stability of Gut

29 Furness, J. B. et al. Nat. Rev. Gastroenterol. Hepatol. 10, (2013) Nutrients Pathogens Metabolites PAMPs Moya, A. and M. Ferrer Functional Redundancy- Induced Stability of Gut Microbiota Subjected to Disturbance. Trends in Microbiology 24: GROWTH IMMUNITY ANTI-STRESS ANTI-OXIDANT

30 Typical high resolution nuclear magnetic resonance (NMR) spectroscopy spectrum of healthy human serum. Numbers indicate the following metabolites: 1, imidazole; 2, urea; 3, D-glucose; 4, L-lactic acid; 5, glycerol; 6, L-glutamine; 7, L-alanine; 8, DSS; 9, glycine; 10, L-glutamic acid; 11, L-valine; 12, L- proline; 13, L-lysine; 14, L-histidine; 15, L-threonine; 16, propylene glycol; 17, L-leucine; 18, L- tyrosine; 19, L-phenylalanine; 20, methanol; 21,creatinine; 22, 3-hydroxybutyric acid; 23, ornithine; 24, L-isoleucine; 25, citric acid; 26, acetic acid; 27, carnitine; 28, 2-hydroxybutyric acid; 29, creatine; 30, betaine; 31, formic acid; 32, isopropyl alcohol; 33, pyruvic acid; 34, choline; 35, acetone; 36, glycerol. Psychogios N, Hau DD, Peng J, Guo AC, et al. (2011) The Human Serum Metabolome. PLoS ONE 6(2): e16957.

of amino acids 9 vitamin digestion and absorption 8 protein digestion and absorption 8 nicotinate and nicotinamide

31 Metabolome and antibiotic growth promoter (AGP) treatment 199 total metabolites were up regulated and statistically significant 114 had KEGG codes 13 Biosynthesis of antibiotics 12 ABC transporters 11 pyrimidine metabolism 10 biosynthesis of amino acids 9 vitamin digestion and absorption 8 protein digestion and absorption 8 nicotinate and nicotinamide methabolism 8arginine and proline metabolism 8 alanine, aspartate and glutamate metabolism 8 b-alanine metabolism 7 histidine metabolism

32 Topics to be discussed Introduction Alternatives to antibiotics Antibiotic alternatives for growth promotion Next steps Conclusions

34 25 partners 4 regional networks Global network of public and private animal health research funders joining efforts to coordinate research on animal health 15 member countries Co-hosts Secretariat Executive Committee Member 50 associated countries Identify priorities Research gap analysis Research roadmaps AMR: Innovative antiinfective approaches Horizon scanning New calls for projects

36 Topics to be discussed Introduction Alternatives to antibiotics Antibiotic alternatives for growth promotion Next steps Conclusions

37 CONCLUSIONS Need to link academia, government researchers, pharmaceutical industry, feed industry, regulatory agencies, and livestock industries Defining the mechanisms of action of alternatives to antibiotics is paramount to enable their effective use, whether they are used for prevention, treatment, or to enhance health and production There is a need to integrate nutrition, health, and disease research A portfolio of alternatives to antibiotics may need to be considered to achieve optimum health and disease management for different animal production systems

University of Gent Karin Hoelzer, Pew Charitable Trust Henk P.

38 Acknowledgement Hyun Lillehoj, USDA-ARS Bruce Seal, Oregon State University Chengbo Yang, University of Manitoba Filip Van Immerseel, University of Gent Karin Hoelzer, Pew Charitable Trust Henk P. Haagsman, Utrecht University Elizabeth Erlacher-Vindel, OIE Faye Ioannou, EMA Cindy Burnsteel, FDA

39 Thank you!

Alternatives to Antibiotics

Alternatives to Antibiotics Cyril Gerard Gay, DVM, PhD Senior National Program Leader Animal Production and Protection Agricultural Research Service cyril.gay@ars.usda.gov Presentation Outline 1. Agricultural