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Cyril G. Gay, DVM, Ph.DSenior National Program LeaderAnimal Production and Protection

The road towards the research and development of alternatives to antibiotics

Topics to be discussed

Introduction

Alternatives to antibiotics

Antibiotic alternatives for growth promotion

Next steps

Conclusions

“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…..”

Alexander FlemingPenicillin

Nobel Lecture, December 11, 1945

Antimicrobial Resistance

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


Introduction



Next steps

Conclusions

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.

Recommendations

http://www.oie.int/eng/A_AMR2013/Recommendations.htm

http://www.oie.int/eng/A_AMR2013/Recommendations.htm

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.

www.ars.usda.gov/alternativestoantibioticsGay 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; 74-75

http://www.ars.usda.gov/alternativestoantibiotics

www.ars.usda.gov/alternativestoantibiotics


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.

Symposium Objectives

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

Symposium Conclusions

• Vaccines• Microbial-derived• Phytochemicals• Immune-related• Innovative drugs


Drugs, biologics, and feed additivesExamples of alternatives to antibiotics


Probiotics as Antibiotic Alternative to Improve Gut Health

Cliniciansbrief.com

Thegutinstitute.com

Lee, K.W., H. Lillehoj, and Siragusa, G. 2010. Direct-Fed Microbials and Their Impact on the Intestinal Microflora and Immune System of Chickens: J. Poultry Science. 47:106-114

Grant A, Gay CG, Lillehoj HS. 2018. Bacillus spp. as direct-fed microbial antibiotic alternatives to enhance growth, immunity, and gut health in poultry. Avian Pathology 47:339-351.

Novel Gene-Editing ToolsUsing 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)

• Vaccines• Microbial-derived therapeutics• Phytochemicals• Immune-related products• Innovative drugs




Phytochemicals – Plant Extracts

From black box to bold science

Wlodarska, M. et al., Sci. Rep. 2015:5:9253. Kim et al., 2011. PLoS One 6:e27712Kim, J, Lillehoj, H. 2015. Res. Vet Sci. 102:150-158.

• Vaccines• Microbial-derived• Phytochemicals• Immune-related• Innovative drugs, chemicals, and enzymes




Homogenized and frozen

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

Lee, SH., Lillehoj, HS. Et al., 2009 veterinary parasitology 163-123-126

Gadde, U., Lillehoj, H., et al., 2015. Passive immunization with hyperim,mune egg yolk IgY as prophylaxis and therapy for poultry diseases- A Review. Animal Health Res Rev 16: 163-176.

Antimicrobial Peptides: NK lysin kills all Apicomplexa


Introduction



Next steps

Conclusions

Antibiotics and their alternatives

Allen HK, et al.Trends in Microbiology March 2013, Vol. 21, No. 3

GROWTH

• Nutrients• Pathogens

Metabolites

PAMPsIMMUNITY ANTI-STRESS ANTI-OXIDANT

Moya, A. and M. Ferrer. 2016. Functional Redundancy-Induced Stability of Gut Microbiota Subjected to Disturbance. Trends in Microbiology 24:402-413

Furness, J. B. et al. Nat. Rev. Gastroenterol. Hepatol. 10, 729–740 (2013)

Typical high resolution nuclear magnetic resonance (NMR) spectroscopy spectrum of healthy human serum.

Psychogios N, Hau DD, Peng J, Guo AC, et al. (2011) The Human Serum Metabolome. PLoS ONE 6(2): e16957.

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.

• 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

Metabolome and antibiotic growth promoter (AGP) treatment


Introduction



Next steps

Conclusions

https://www.biomedcentral.com/collections/alternatives-to-antibiotics

https://www.sciencedirect.com/science/article/pii/S1045105618300587?via%3Dihub

Global network of public and privateanimal health research funders joining

efforts to coordinate research on animal health

Research gap analysis

Research roadmaps

Identify priorities

Co-hosts Secretariat

Executive Committee Member

New calls for projects

AMR:Innovative anti-

infective approaches

Horizon scanning

4 regional networks

25 partners

15 member countries

50 associated countries

www.star-idaz.net

https://www.ars.usda.gov/alternativestoantibiotics/


Introduction



Next steps

Conclusions

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



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

Thank you!

[email protected]

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