Alternatives to Antibiotics: Recent scientific development · Alternatives to Antibiotics: Recent...

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Alternatives to Antibiotics: Recent scientific development Cyril G. Gay, DVM, Ph.D National Program Leader Animal Production and Protection Agricultural Research Service United S Department of Agriculture [email protected]

Transcript of Alternatives to Antibiotics: Recent scientific development · Alternatives to Antibiotics: Recent...

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Alternatives to Antibiotics:

Recent scientific development

Cyril G. Gay, DVM, Ph.D

National Program Leader

Animal Production and Protection

Agricultural Research Service

United S Department of Agriculture

[email protected]

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Antibiotic Use in Food Animals

• Therapeutic - treatment of diseased animal

• Prophylactic - disease prevention

• Metaphylactic - therapeutic and prophylactic use

• Growth promotion – accelerate growth of animals

• Regardless of personal opinions:

• Increasing concern with antibiotic resistance

• Increased regulation – ban of some antibiotics

• Examination of alternatives to conventional

antibiotics is warranted

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www.ars.usda.gov/alternativestoantibiotics

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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

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Vaccines, probiotics, prebiotics, phytochemicals, essential

oils, heavy metals, organic acids, bacteriophage,

bacteriophage gene products, host-derived antimicrobials,

small interfering RNAs, naturally occuring antibacterial

lytic enzymes, recombinant and hyperimmune therapeutic

antibodies, immune enhancers

www.ars.usda.gov/alternativestoantibiotics

What are alternatives to antibiotics?

Drugs, biologics, biotherapeutics, feed additives

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1. Alternatives: Lessons from nature

2. Immune modulation approaches

3. The gut microbiome – microbial ecology

4. Alternatives for growth promotion

5. Regulatory pathways to enable licensing

of novel alternatives to antibiotics

Symposium Organization

Five Major Topics

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Aim of this session was to review novel alternative

approaches for preventing and/or treating bacterial

pathogens (and where applicable viral and

parasitic pathogens) in food animal production.

Alternatives to Antibiotics: Lessons from Nature

SESSION 1

www.ars.usda.gov/alternativestoantibiotics

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Plant virus e.g., Tobacco mosaic virus

Bacteriophage e.g., T1, T2, T4,

Animal virus e.g., Influenza, HIV

Human

Poultry Swine

Bacteriophage

Bacteria Specific

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Bacteriophage

• Discovered by Felix d’Herelle in 1917

• Infect and replicate in bacterial cells

• Host specific infections

• Must enter and exit bacterial host cell

• Lytic cycle and lysogenic cycle

• DNA and RNA phages

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Bacteriophage as an Intervention

• Felix d’Herelle explored using phage solutions to treat

dysentery in humans during early 1900’s

• Phages supplied to Russian soldiers during World War II

• Republic of Georgia using phage therapy since the 1940s

• In 2006, US FDA approved Listeria phage solution for

using in ready-to-eat meat & poultry

• In 2011, US FDA approved E. coli phage for using on food

• Possible therapy for multi-drug-resistant strains of bacteria

Bacteriophages: the alternatives to antibiotics for animal feed

Jae-Won Kim, CJ Research Institute of Biotechnology, CJ Cheiljedang, Seoul, Republic

of Korea

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Bacteriophage

Challenges

Restriction modification – degradation

of phage DNA upon infection

CRISPR – clustered regularly

interspaced short palindromic repeats

Immunogenicity – antibodies developed

against phage

Resistance – mutations in bacterial

genes for adsorption and lysogeny

Lateral Gene Transfer – virulence

factors & antibiotic resistance Bacteriophage Resistance Mechanisms

Labrie et al. Nat Rev Micro 8(5):317, 2010

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Bacterial cell wall and murein hydrolases from Hermoso et al., Curr Opin Microbiol 10:461, 2007

Amidases

Muramidase

(Lysozyme)

Glucosaminidases

Endopeptidases

Holins form lesions in

bacterial membranes

are involved with

release of phage

Autolysins and

prophage enzymes

present in genomes

of bacteria

Bacteriophage Gene Products

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Gel Electrophoresis and Spot Assay with

Clostridium perfringes Bacteriophage Lysin

Lysin

Lysostaphin Lysozyme

Control

Lane 1 – molecular weight markers

Lane 2 – induced E. coli lysate

Lane 3 – nickel purified phage lysin

Spot assays are conducted with E. coli

lysate or purified recombinant lysin as

compared to lysostaphin and lysozyme

NOTE clear zone of complete lysis

20kD

25kD

C. perfringens

Strain 39 host

Seal et al. Arch Virol 156:25, 2011

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Bacteriophage Gene Products

• Phage genomics-proteomics to search

for potential novel antimicrobials

• Bacteriophage lytic enzymes

• Amidase

• Muramidase

• Endopeptidase

• Recombinant phage enzymes lytic

against Clostridium perfringens

• Chimeric phage lysins act

synergistically against Staph. Aureus

• Challenges - Need efficient and cost-

effective expression system

Seal et al. Arch Virol

156:25, 2011

Schmelcher et al. Appl

Environ Microbiol.

78(7):2297-305. 2012

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Animal-derived antimicrobial peptides (APM)

“Innate host defense”

• Present in all organisms

• Ancient Snake: cathelicidin

Frog: plastrin

Insect: cecropin

Bacteria: bacteriocins

• Limited repertoire

• Rapid acting

• Broad specificity

• Constitutive and Stimulated

Cellular defenses

Effector molecules

Neutrophils

Macrophages

NK-cells

Enzymes

Host Defense Peptides

Collectins

“The first line of defense against infection”

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Chicken Cathelicidin 2 (Cath-2)

• Cationic

• 26 amino acids

• Amphipathic

C-RFGRFLRKIRRFRPKVTITIQGSARF-NH2

Hinge region

N

C Van Dijk et al., 2005

Xiao et al., 2006

Henk P. Haagsman

Department of Infectious Diseases and Immunology, Utrecht University, The Netherlands

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Heterophils

Mononuclear

Cells

Giemsa Anti-CATH-2 Van Dijk et al., 2009

Chicken Cathelicidin 2 (Cath-2)

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Chicken Cathelicidin 2

Conclusions

• Salmonella enteritidis infections of chickens - accumulation

of CATH-2 heterophils at site of infection

• CATH-2 is microbiocidal against Gram (-), Gram (+)

bacteria, yeasts and fungi

• Truncated CATH-2 analogs are also antimicrobial

• CATH-2 and derived peptides induce cytokine production in

a chicken macrophage cell line

• CATH-2 reduces the LPS-induced inflammatory response

• Prophylactic or therapeutic treatment of chickens with

CATH-2 significantly reduced Salmonella survival in the crop

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Development of Cathelicidin 2

Challenges

• Improve specific activities of compounds

• Improve stability of lead structures

• Development carrier/delivery systems

• Pharmacokinetics

• Cost-effective large scale production

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• Most tested AMPs kill bacteria by membrane disruption. Some

AMPs may have intracellular targets

• Some AMPs show strong activity with high cytotoxicity, while some

AMPs show low cytotoxicity with weak activity

• AMPs with more potent activity and lower cytotoxicity will be

obtained through screening and molecular design

• The expression level of recombinant peptides needs to be improved

dramatically in order to apply AMPs into animal production

• More attention needs to be paid to how to enhance the expression

of endogenous AMPs through nutritional regulation

Animal-derived antimicrobial peptides (AMPs)

Conclusions

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Treatment strategy that will allow the maintenance of high-titer

antibodies against parasites in the gut showed protective effects

Lee, SH., Lillehoj, HS. et al., 2009 Poultry Science 88:562-566 Lee, SH., Lillehoj, HS. et al., 2009 Veterinary Parasitology 163-123-126

385

390

395

400

405

410

415

420

body

weight

(gm)

Control Eimeria IgY Low IgY High

Passive immunity using hyperimmune IgY

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Aim of this session was to address novel drug-free

strategies to enhance innate defense mechanisms

and/or adaptive immune responses by modulation of

immune pathways through immune sensing molecules.

www.ars.usda.gov/alternativestoantibiotics

SESSION 2

Immune Modulation Approaches to Enhance

Disease Resistance and Treat Animal Infections

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Bali Pulendran and David Artis. 2012, New Paradigms in Type 2 Immunity. Science 337, 431.

Diversity of stimuli can bind host conserved recognition receptors (PRRs=

Pattern Recognition Receptors) and stimulate immune response

Innate sensing receptors PRRs TLRs NLRs RIG-1

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Some phytochemicals (essential oils) interact with

host PRRs and initiate inflammatory immune response

PRRs: TLRs, NODs

Bioactive phytochemicals

DAMPs (Necrotic cell products)

PAMPs (Pathogens, diets)

Innate immune response

Dysregulated immune response

-Host resistance -Wound healing

-Cancer -Atherosclerosis -Insulin resistance Inflammation

Level of PRR activation

PRRs and downstream signaling components are molecular targets for dietary intervention strategies using phytochemicals to reduce PRR-mediated inflammation

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Dietary supplementation with phytonutrients such as

safflower leaf, plum, anethol, mushroom, capsaicin,

cinnamaldehyde, tumeric , garlic, etc.

Enhance innate immunity

Lee, S.H. et al., 2008, 2009, 2010, 2011,2012

Phytochemicals – Plant Extracts

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Gene Ontology categories 5 ppm carvacrol

3 ppm cinnamaldehyde

2 ppm capsicum

N of genes which expression…

- is altered 74 62 254

- is up regulated 26 31 98

- is down regulated 48 31 156

Examples of GO Categories for:

- General metabolism 13 12 51

- protein metabolism, 8 16 26

- Signal transduction 7 10 31

- Nucleic acid metabolism 5 14 25

- Immunity and defense 7 6 16

KIM, DK, Lillehoj, HS, et al., 2010. Poul Sci 89:68-81

Functional Genomics

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Phytochemicals

Challenges

• Conducting a “general” evaluation of the

effect of phytonutrients on production

performance is difficult

• Few published studies are available; often

papers provide minimal description of additive

composition or active ingredients

• Phytochemicals are very distinct molecules,

with different effects, doses and mechanisms

of action, and need to be developed

accordingly

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www.ars.usda.gov/alternativestoantibiotics

SESSION 3

The Gut Microbiome and

Immune Development, Health and Disease

Recent advances are demonstrating that the gut microbiota plays

a key role in health and disease.

Aim of this session was to capture state-of-the-art results in farm

animals and humans to assess how the gut microbiome analysis

is helping to solve disease problems.

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Bacteriotherapy

• Pathological imbalances within

the intestinal microbiota, termed

dysbiosis, are often associated

with chronic Clostridium difficile

infections in humans

• Fecal transplantation, the

administration of homogenized

feces from a healthy donor, is a

promising alternative therapy

• Bacteriotherapy was shown to be

a viable therapeutic target to

treat chronic C. difficile infections

and potentially other forms of

persistent dysbiosis Lawley T.D et al. PLoS Pathog.

2012 October; 8(10): e1002995

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Metabolomics

DNA Microbiome or

Virome

RNA Metagenomics

Metatranscriptomics

16s Survey

Microbiome and Metagenomic Analysis

The ruminal microbiome and animal health

John Wallace, Rowett Institute of Nutrition and Health, UK

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Microbial genomics

• Genomics and metagenomics

approaches to understand host-

environment-microbe interactions

• Evaluation of host response patterns

to a single pathogen versus

commensal flora

• Assess the role of the commensal

flora as a protective barrier against

invading pathogens

• Elucidate how commensal

organisms or probiotics can be used

to prevent or treat infections

Demuth A et al., Infect Genet Evol. 2008

May;8(3):386-93. Epub 2008 Jan 18. Review.

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Probiotics

• Work through the competitive exclusion of pathogenic bacteria

• Promoting epithelial barrier integrity

• Influence the host and its gut microbiota by affecting many aspects

of the immune system

• Regulation of local mucosal cell-mediated immune responses

• Increasing antibody production

• Reducing epithelial programmed cell death (apoptosis)

• Enhancing dendritic cell-induced T cell responses

• Improving T cell homing to mesenteric lymph nodes

• Augmenting toll-like receptor signaling

Lee et al., 2010. J. Poul. Sci 47:106-114.

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Gastrointestinal Microbiome

• Bacteria, fungi, viruses,

protozoa, helminths

• Bacteria 1011 cells/gram

• Firmicutes

• Bacteroidetes

• Proteobacteria

• Bacteria primarily

associated with mucus and

macromolecular food matrix

(fiber)

• Composition varies

• In different section of GI

• In different animals

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Integrating nutrition, health and

disease research

• Science of nutrition

• Improved feed

efficiency

• Improved growth

rates

• Assess alternative

feeds

• Science of disease

• Prevent intestinal

diseases

• Reduce inflammation

• Prevent colonization

of foodborne

pathogens

• Reduce shedding of

pathogens

• Increase disease

resistance

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www.ars.usda.gov/alternativestoantibiotics

SESSION 4

Alternatives to Antibiotics to Promote Growth in

Livestock, Poultry, and Aquaculture Production

Aim of this session was to explore novel approaches that can

be used as alternatives for antimicrobial growth promoters

during food-animal production.

Another key aim was to improve knowledge on mechanisms

of action of the growth-promoting characteristics of the

proposed approaches.

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Antibiotics growth promoters (AGP): How do they work?

Anti-microbial Anti-inflammatory

Dibner, J.J., & Richards, J.D. 2005. Poul. Sci.

84:634-643.

Niewold, T.A. 2007. Poul. Sci. 86:605-609.

Antibiotics growth promoters (AGP)

How do they work?

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Phytochemicals for growth promotion

Conclusions

• The use of phytochemicals in animal feeds to

enhance growth and feed efficiency is a

potential alternatives strategy to antimicrobial

growth promoters

• Phytochemicals are very diverse molecules

and an increasing number of publications are

documenting their efficacy

• Research to understand their mode of action

is paramount to achieve improved product

consistency, consumer acceptance, and

global use

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www.ars.usda.gov/alternativestoantibiotics

SESSION 5

Regulatory Pathways to Enable the Licensing of

Alternatives to Antibiotics

Aim of this session was to review regulatory pathways in different

regions of the world to license alternatives to antibiotics.

Regulatory challenges that are faced in taking new molecules

from discovery to commercial production was reviewed.

Session also covered how to seek approval for labeling claims

that a product is able to reduce use of antibiotics

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• Alternatives to antibiotics will be regulated as a drugs, biologics,

feed additives

• Alternatives to antibiotics must be developed according to

national and international standards and meet

requirements for efficacy, safety, and quality

• Regulatory processes are in place to enable and facilitate the

licensing of alternatives to antibiotics

• Need to engage regulatory agencies early in the process

CONCLUSIONS FROM SESSION 5

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Conclusion:

Antibiotics and their alternatives

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

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Future Direction

• Integrating nutrition, health, and disease research will be

driven by technological advances and the application of

the “omic” fields in animal agriculture research

• These technological advances will include new research

tools and opportunities that afford scientists a hitherto

unprecedented ability to discern the mechanisms by which

alternatives to antibiotics can be used to develop

strategies to enhance the health, productivity and welfare

of animals

FUTURE DIRECTIONS

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Future Direction

• There is a critical need for developing novel antimicrobials

and alternative strategies for preventing and treating

infectious diseases to safeguard the use of currently

available antibiotics but importantly meet the challenges of

antimicrobial resistance

• We need to establish partnerships between academic and

government researchers with the feeds and pharmaceutical

industries and their regulators to enable the development of

effective and safe alternatives to antibiotics

FUTURE DIRECTIONS

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Future Direction

• Understanding the ecology of antimicrobial resistance will

remain a critical endeavor

• But we need to garner the support of stakeholders, funders,

public and government institutions to pay equal attention to

problem-solving, such as developing technologies that are

more resillient to antimicrobial resistance and alternative

strategies to enhance the health and welfare of animals.

FUTURE DIRECTIONS

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Thank you!

[email protected]

www.usda.ars.gov

www.ars.usda.gov/alternativestoantibiotics