antimicrobial resistance (amr) - genomic options to advance canada’s action plan david bailey,...
TRANSCRIPT
Antimicrobial Resistance (AMR) -Genomic Options to Advance Canada’s Action Plan
David Bailey, Ph.D.
President and CEOGenome Alberta
Beef Value Chain Roundtable (BVCRT)Ottawa, Ontario4-5 March 2015
Beef Value Chain Roundtable (Ottawa, Ontario)
2
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)
4-5 March 2015
Beef Value Chain Roundtable (Ottawa, Ontario)
3
Outline
Overview - Antimicrobial Resistance (AMR)
Canada’s AMR Action Plan - Key Focus Areas
Genomic Options
Closing Remarks
4-5 March 2015
Beef Value Chain Roundtable (Ottawa, Ontario)
4
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)
4-5 March 2015
The Economist (31-MAR-2011)
Beef Value Chain Roundtable (Ottawa, Ontario)
5
Overview - AMR
Is Resistance A Natural Phenomenon?
YES - Evolution of resistant
strains is a natural
phenomenon but the use
and misuse of antimicrobial
drugs accelerates the
emergence of drug-resistant
strains.
~ WHO Fact Sheet No. 194 (2014)
4-5 March 2015
~ S
chm
iede
r an
d E
dwar
ds (
2012
)
“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)
Beef Value Chain Roundtable (Ottawa, Ontario)
6
“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
Overview - AMR
How Does Resistance Develop?
4-5 March 2015
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
Beef Value Chain Roundtable (Ottawa, Ontario)
7
(1) VERTICAL
Natural resistance OR Spontaneous mutation
(2) HORIZONTAL
Horizontal transfer of AMR genes to same or different microbes
Overview - AMR
How is Antimicrobial Resistance Transferred?
4-5 March 2015
Bacteria have a new generation
every 20 minutes!~ Dame Sally Davies
2015
AMR AMR
Mobile Genetic Elements
Beef Value Chain Roundtable (Ottawa, Ontario)
8
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.
4-5 March 2015
-- Antimicrobial Resistance – Global Report on Surveillance (World Health Organization, 2014)
“bacteria do not recognize borders”– National (USA) Strategy for Combating Antibiotic-Resistant Bacteria (Sep 2014)
Beef Value Chain Roundtable (Ottawa, Ontario)
9
Overview - AMR
Link between AMR in Humans and Livestock?
“Substantial evidence demonstrates that
use of antibiotics in animal agriculture
promotes the development of antibiotic-
resistant 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)
4-5 March 2015
“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
Beef Value Chain Roundtable (Ottawa, Ontario)
10
Canada’s AMR Action Plan - Key Focus Areas
A Federal Framework For Action
4-5 March 2015
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.
Beef Value Chain Roundtable (Ottawa, Ontario)
11
Genomic Options
Gene? Genome? Genomics?
4-5 March 2015
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.
Beef Value Chain Roundtable (Ottawa, Ontario)
12
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
Genomic Options
Growth Promotion & Disease Control
4-5 March 2015
Eliminate use of antimicrobials for growth promotion Reduce reliance on antimicrobials for disease control
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
13
Antimicrobial Growth Promotants
As intended, total antimicrobial use in livestock dropped.
But use of prescribed antimicrobials in livestock went up!
14
Cattle drug sales in Denmarksince 2001
Very High Importance High Importance Medium Importance0
10
20
30
40
50
60
70
2001200220032004200520062007200820092010
% o
f a
nti
mic
rob
ials
so
ld b
y
fee
dm
ills
an
d p
ha
rma
cie
s
Beef Value Chain Roundtable (Ottawa, Ontario)
15
Genomic Options
Treat INDIVIDUALS, not all
Adopt animal management practices and technologies that quickly identify sick individuals for closer inspection and treatment.
4-5 March 2015
Stop misuse and abuse of antimicrobials
Feed intake & behaviour monitoringPrecision Livestock Farming – “Virtual Shepherd”
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.
Track Temperature
Beef Value Chain Roundtable (Ottawa, Ontario)
16
Genomic Options
Miniaturized Equipment
4-5 March 2015
Point-of-need ID of microbes and treatment with correct antimicrobials
Methods of Identifying Microbes
(1) Biochemical
(2) Genetic tools (PCR, DNA fingerprinting)
(3) Spectral analysis (mass spectrometry, elastic light scattering,)
Laboratory Field
Miniaturize?
Point-of-need ID of microbes
E. coli
Beef Value Chain Roundtable (Ottawa, Ontario)
17
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
Genomic Options
Nano-based Solutions
4-5 March 2015
Preventive Measures / Diagnosis / Therapies
Beef Value Chain Roundtable (Ottawa, Ontario)
Genomic Options
DNA Barcoding
4-5 March 2015
18
Rapid ID of microbes and treatment with correct antimicrobials
Animal Groups Land Plants
matK(1500 bp)rbcL
CO1(648 bp)
Microbes
• Chaperonin-60 (cpn60)
• ?
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.
Beef Value Chain Roundtable (Ottawa, Ontario)
19
Most antibiotics were discovered by screening cultivable soil microorganisms
PROBLEM SOLUTION
1% cultivable 99% NOT cultivable
iChip – isolate and grow uncultured bacteria in native soil
Genomic Options
Discover New Antibiotics
4-5 March 2015
End 30-year “discovery void”
50% cultivable
A New Antibiotic (Teixobactin) Kills
Pathogens Without Detectable Resistance
Ling, et. al. (2015)
NEW peptidoglycan synthesis inhibitor
Beef Value Chain Roundtable (Ottawa, Ontario)
20
Construct full-length cDNA of PEDV
Introduce attenuating mutations
Introduce strategic
DIVA mutations
Produce new vaccine
Genomic Options
New Vaccines / Therapeutics / Combinations
4-5 March 2015
Reduce reliance on antimicrobials and promote health
New Vaccines‘Smart Vaccines’ use reverse genomics to develop vaccines.
Porcine Epidemic Diarrhea Virus (PEDV)
~ VIDO-Intervac University of Saskatchewan
Therapeutics 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,
Combination Therapies Combination therapies that target both
essential functions and resistance
factors are also promising
Differentiate Infected from Vaccinated Animals
21
Genomic Options
Modern Tools for a Growing Challenge
4-5 March 2015Beef Value Chain Roundtable (Ottawa, Ontario)
Genomic technologies can be used…
To develop novel antibioticsMicrobial whole-genome sequencing (WGS) allows for rapid id of resistance mechanisms
For surveillanceMicrobial 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
22
Closing Remarks
4-5 March 2015Beef Value Chain Roundtable (Ottawa, Ontario)
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