Antimicrobial Resistance (AMR) Genomic Options to Advance Canada’s Action Plan
David Bailey, Ph.D.
President and CEO
Genome Alberta
Beef Value Chain Roundtable (BVCRT)
Ottawa, Ontario
4-5 March 2015
Beef Value Chain Roundtable (Ottawa, Ontario)
4-5 March 2015
No Antimicrobials – What Would That Mean?
 “If antibiotics stopped working, we would find that instead of 7% of deaths
being related to infection at the moment in the developed world, it would go
back up to about half (50%) of deaths, just because we couldn’t use
antibiotics.” ~ Dame Sally Davies, UK Chief Medical Officer (Feb 2015)
 “In a world with few effective antibiotics, modern medical advances such as
surgery, transplants, and chemotherapy may no longer be viable due to the
threat of infection”
~ (USA) National Strategy for Combating Antibiotic-Resistant Bacteria (Sep 2014)
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Beef Value Chain Roundtable (Ottawa, Ontario)
4-5 March 2015
Outline
 Overview - Antimicrobial Resistance (AMR)
 Canada’s AMR Action Plan - Key Focus Areas
 Genomic Options
 Closing Remarks
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Beef Value Chain Roundtable (Ottawa, Ontario)
4-5 March 2015
Overview - AMR
What is Antimicrobial Resistance?
Resistance of a microbe (bacteria, fungi, viruses, parasites) to an
antimicrobial drug that was originally effective for treatment of
infections caused by it.
~ WHO Fact Sheet No. 194 (2014)
The Economist (31-MAR2011)
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Beef Value Chain Roundtable (Ottawa, Ontario)
4-5 March 2015
Overview - AMR
YES - Evolution of resistant
strains is a natural
phenomenon but the use
and misuse of antimicrobial
drugs accelerates the
~ Schmieder and Edwards (2012)
Is Resistance A Natural Phenomenon?
emergence of drug-
resistant strains.
~ WHO Fact Sheet No. 194 (2014)
“There has been a seven-fold increase in the incidence of Vancomycin-resistant
Enterococci infections between 2007-2012.”– AMR and Use in Canada (Oct 2014)
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Beef Value Chain Roundtable (Ottawa, Ontario)
4-5 March 2015
Overview - AMR
How Does Resistance Develop?
“Resistome”
The collection of all genes that directly
or indirectly contribute to antibiotic
resistance.
Categories
(1) Inactivation (of genes)  bacteria
more resistant to antibiotics
(2) Inactivation (of genes)  bacteria
more susceptible to antibiotics
Resistance Mechanisms
1. Produce enzyme that degrades
antibiotic (= antibiotic inactivation)
2. Produce enzyme that alters
antibiotic (= target site alteration)
3. Overproduce antibiotic targets
(= target amplification)
4. Reduce intracellular accumulation
of antibiotic ( influx,  efflux)
… option to improve
efficacy of current drugs
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Beef Value Chain Roundtable (Ottawa, Ontario)
4-5 March 2015
Overview - AMR
How is Antimicrobial Resistance Transferred?
(1) VERTICAL
(2) HORIZONTAL
Natural resistance OR
Spontaneous mutation
Horizontal transfer of AMR genes
to same or different microbes
Mobile Genetic Elements
AMR
AMR
Bacteria have a
new generation
every 20 minutes!
~ Dame Sally Davies
2015
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Beef Value Chain Roundtable (Ottawa, Ontario)
4-5 March 2015
Overview - AMR
Why is AMR a Global Health Concern?
The rate at which
microbes are acquiring
resistance is GREATER
than the rate at which
antimicrobials are being
discovered.
“bacteria do not recognize borders”
– National (USA) Strategy for Combating
Antibiotic-Resistant Bacteria (Sep 2014)
-- Antimicrobial Resistance – Global Report on Surveillance (World Health Organization, 2014)
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Beef Value Chain Roundtable (Ottawa, Ontario)
4-5 March 2015
Overview - AMR
Link between AMR in Humans and Livestock?
 “Substantial evidence demonstrates that
use of antibiotics in animal agriculture
promotes the development of antibioticresistant microbes in animals and that
retail meat can be a source of microbes,
including antibiotic-resistant microbes” ~
Report to the (USA) President on Combating Antibiotic Resistance
(Sep 2014)
 Transfer of resistant microbes between
humans and livestock does occur
(genomics is helping to prove this point)
“Worldwide, over 70% of
all antibiotics prescribed
are used on farm animals”
~ Dame Sally Davies 2015
“Up to half of antibiotic use in
humans and much of antibiotic
use in animals is unnecessary
and inappropriate and makes
everyone less safe.”
~ CDC 2013
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Beef Value Chain Roundtable (Ottawa, Ontario)
4-5 March 2015
Canada’s AMR Action Plan - Key Focus Areas
A Federal Framework For Action
SURVEILLANCE
Detecting and monitoring trends and threats in order to
inform strategies to reduce the risks and impacts of
antimicrobial resistance (CNISP, CIPARS, CARSS)
STEWARDSHIP
Conserving the effectiveness of existing treatments
through infection prevention and control guidelines,
education and awareness, regulations, and oversight.
INNOVATION
Creating new solutions to counteract loss in
antimicrobial effectiveness through research and
development.
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4-5 March 2015
Genomic Options
Gene? Genome? Genomics?
Gene is the basic physical and functional unit of heredity. Genes,
which are made up of DNA, act as instructions to make molecules
called proteins.
Genome is the complete set of genes or genetic material in a cell or
organism.
Genomics is the study of the structure, content, and evolution of
genomes, and includes analysis of the expression and function of
both genes and proteins.
Epigenetics relates to, or arises from, non-genetic influences on gene
expression.
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Genomic Options
Growth Promotion & Disease Control
 Eliminate use of antimicrobials for growth promotion
 Reduce reliance on antimicrobials for disease control
 Targeted manipulation of gut microbiome to promote growth
 Probiotics inhibit pathogens by competing for colonization sites
or nutritional sources
 Prebiotics selectively stimulate activity of a limited number of
bacteria in colon, which promotes growth
 Replacement breeding stock selected for fast and efficient growth
 Continue search for compounds that could (?) replace antibiotics
 Immunity modulating agents, bacteriophages & lysins,
phytodynamic
therapy (PDT), antimicrobial peptides (AMPs), pro-/pre-/synbiotics,
plant extracts, inhibitors targeting pathogenicity, feed enzymes, …
 Improved infection control measures
 Promote vaccine use
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Antimicrobial Growth Promotants
But use of
prescribed
antimicrobials
in livestock
went up!
As intended,
total
antimicrobial
use in livestock
dropped.
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Cattle drug sales in Denmark
since 2001
% of antimicrobials sold by
feedmills and pharmacies
70
60
2001
2002
50
2003
2004
40
2005
2006
30
2007
2008
20
2009
10
2010
0
Very High Importance
High Importance
Medium Importance
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4-5 March 2015
Genomic Options
Treat INDIVIDUALS, not all
 Stop misuse and abuse of antimicrobials
Adopt animal management practices and technologies that quickly
identify sick individuals for closer inspection and treatment.
AMR and Use in Canada
– A Federal Framework for Action
ACTION 3: Work with the animal agriculture
sector partners to strengthen the regulatory
framework on veterinary medicines and
medicated feeds, including facilitating
access to alternatives and encourage the
adoption of practices in order to reduce the
use of antimicrobials.
Feed intake & behaviour monitoring
Precision Livestock Farming – “Virtual Shepherd”
Track Temperature
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Beef Value Chain Roundtable (Ottawa, Ontario)
4-5 March 2015
Genomic Options
Miniaturized Equipment
 Point-of-need ID of microbes and treatment with correct antimicrobials
Methods of Identifying Microbes
(1) Biochemical
(2) Genetic tools (PCR, DNA
fingerprinting)
Miniaturize?
E. coli
(3) Spectral analysis (mass
spectrometry, elastic light scattering,)
Laboratory
Field
Point-of-need
ID of microbes
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Beef Value Chain Roundtable (Ottawa, Ontario)
4-5 March 2015
Genomic Options
Nano-based Solutions
 Preventive Measures / Diagnosis / Therapies
Nanocoatings
•
•
OxiTitan – mineral based photocatalyst solution applied to textiles and
surfaces has proven action against AMR bacteria ( C. Difficile 10x in 24h)
Nanoporous magnetic-like coating can trap and kill superbugs (S. aureus, )
Nanoparticles, nanosensors, nanocrystals, nanomechanical,
•
•
Accurate, economical, less time-consuming methods of detecting microbes
Targeted delivery of nanomedicines using bispecific antibodies
Nano-metals (Ag, Au, Fe, Cu) and metallic oxides (Ag2O, TiO2, ZnO, …)
•
Metal nanoparticles are effective against a broad spectrum of AMR bacteria
Nano-enabled antibiotics
•
A variety of nanosized carriers can be used as
drug delivery systems
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Beef Value Chain Roundtable (Ottawa, Ontario)
4-5 March 2015
Genomic Options
DNA Barcoding
 Rapid ID of microbes and treatment with correct antimicrobials
DNA barcoding is a technique for characterizing species of
organisms using a short DNA sequence from a standard and
agreed-upon position in the genome. DNA barcode sequences
are very short relative to the entire genome and they can be
obtained reasonably quickly and cheaply.
Animal Groups
Land Plants
matK
(1500 bp)
rbcL
Microbes
•
Chaperonin-60
(cpn60)
•
?
CO1
(648 bp)
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Beef Value Chain Roundtable (Ottawa, Ontario)
4-5 March 2015
Genomic Options
Discover New Antibiotics
 End 30-year “discovery void”
Most antibiotics were discovered by
screening cultivable soil microorganisms
PROBLEM
SOLUTION
50%
cultivable
1% cultivable
99% NOT
cultivable
iChip – isolate and
grow uncultured
bacteria in native soil
A New Antibiotic
(Teixobactin) Kills
Pathogens Without
Detectable Resistance
Ling, et. al. (2015)
NEW peptidoglycan
synthesis inhibitor
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Beef Value Chain Roundtable (Ottawa, Ontario)
4-5 March 2015
Genomic Options
New Vaccines / Therapeutics / Combinations
 Reduce reliance on antimicrobials and promote health
New Vaccines
Therapeutics
‘Smart Vaccines’ use reverse genomics to develop
vaccines.

Investigate candidates that interrupt
bacterial protein synthesis or disrupt
bacterial cell wall

Alternatives to small molecule
antibiotics: monoclonal antibodies,
synthetic antibodies, small inhibitory
oligonucleotides, antibacterial
peptides,
Porcine Epidemic Diarrhea Virus (PEDV)
~ VIDO-Intervac University of Saskatchewan
Combination Therapies
Construct
full-length
cDNA of
PEDV
Introduce
attenuating
mutations
Introduce
strategic
DIVA
mutations
Produce
new
vaccine

Combination therapies that target
both essential functions and
resistance factors are also promising
Differentiate Infected from
Vaccinated Animals
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Beef Value Chain Roundtable (Ottawa, Ontario)
4-5 March 2015
Genomic Options
Modern Tools for a Growing Challenge
Genomic technologies can be used…
 To develop novel antibiotics
Microbial whole-genome sequencing (WGS) allows for rapid id of resistance mechanisms
 For surveillance
Microbial WGS provides insight into the history of emergence and spread of AMR
 To study emergence of antibiotic resistance in real-time
 To develop diagnostic tests and direct infection control measures
 To study “Resistome”

Predict evolution of resistance

Understand link between resistance and virulence

Defining novel targets which inactivation make bacteria more susceptible to antibiotics
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Beef Value Chain Roundtable (Ottawa, Ontario)
4-5 March 2015
Closing Remarks
Genomic Options








Growth promotion and disease control
Treat INDIVIDUALS, not all
Miniaturized Equipment
Nano-based solutions
DNA barcoding
Discover new antibiotics
New vaccines / Therapeutics / Combinations
Modern tools for a Growing Challenge
Solutions to AMR will require new and creative ways of
thinking, the integration of technologies and management
practices, and research investment dollars
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Beef Value Chain Roundtable (Ottawa, Ontario)
4-5 March 2015
Thank You
Acknowledgments
 Susan Joyal – Consultant
 Tim McAllister – AAFC
 Reynold Bergen – BCRC
 Cindy Bell – Genome Canada
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