Dr Steven Cobb
The superbugs are
coming!
The race for new antibiotics
Chemistry Department
Durham University
s.l.cobb@durham.ac.uk
Bacterial resistance and the
generation of superbugs
Bacteria: Friend or Foe?
Fighting infectious bacteria
Is the situation really that bad?
Introducing antibiotics and the
bacteria cell
Antibiotics of the future: Research
at Durham
Penicillin: The wonder drug
Summary
Vancomycin: The antibiotic of last
resort
Antibiotics beyond 2011
Dr S. Cobb/ Durham University
1
Bacteria: Friend or Foe?
Infectious bacteria (bad bacteria)
Probiotic bacteria
(good bacteria)
Dr S. Cobb/ Durham University
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Fighting infectious bacteria
Cure
Prevention
Rest
Time
Antibiotics (drug molecules)
Dr S. Cobb/ Durham University
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What are antibiotics?
Antibiotics are compounds that can be used to kill bacterial
cells.
Sulfonamide drugs (late 1930s)
Penicillin (-lactams, 1940s)
Vancomycin (late 1950s)
Dr S. Cobb/ Durham University
4
Antibiotic targets
The cell is the most basic building block for life in all
organisms.
Structural differences between cell types (e.g. human and
bacteria) can be used to design selective drugs.
This has been carried out to great effect in the development
of antibiotics.
Dr S. Cobb/ Durham University
5
Human and bacterial cells
Normal human cell
Plasma Membrane (no cell wall)
Dr S. Cobb/ Durham University
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Antibiotics and the magic bullet effect
Normal cells
Bacteria
Antibiotic
Bacteria are
killed and the
normal cells left
untouched
Dr S. Cobb/ Durham University
7
Penicillin: The wonder drug of the 20th century
The Nobel Prize in Physiology
or Medicine 1945
Sir Alexander Fleming, Ernst
Chain, Sir Howard Florey
Ernst Chain
Howard Florey
Dr S. Cobb/ Durham University
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Penicillin’s mode action against bacteria
Dr S. Cobb/ Durham University
9
Penicillin’s mode action against bacteria
Dr S. Cobb/ Durham University
10
Penicillin: The wonder drug of the 20th century
Advantages
Relatively inexpensive (compared to alternatives).
In general non-toxic to patient.
Disadvantages
Not active against a broad spectrum of bacteria and not effective against
Gram-negative bacteria.
Unstable to acidic conditions thus can not be given in oral form.
Simple mutations in bacteria can give rise to penicillin resistant strains.
Can cause allergic reactions in some people (1-4% cases) which can be
very serious. Fatality rates however are low 0.001%.
Dr S. Cobb/ Durham University
11
Vancomycin: The antibiotic of last resort
Scientists realized that Vancomycin
was active against bacterial strains
that had developed resistance to
Penicillin-based drugs.
Fast tracked by the FDA and since
1958, it has been a key player in the
war against bacterial pathogens.
It is commonly used when other
drugs fail and thus it is widely known
as the “antibiotic of last resort”.
Vancomycin is a glyco-peptide
(sugar-peptide) that was first
isolated from Borneo jungle soil
samples.
Dr S. Cobb/ Durham University
12
Vancomycin: Mode of action
Dr S. Cobb/ Durham University
13
Antibacterial resistance and the generation of superbugs
Dr S. Cobb/ Durham University
14
Penicillin and antibacterial resistance
Emergence of bacterial
resistance to Penicillin
detected as earlier as 1948
Dr S. Cobb/ Durham University
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What causes bacterial resistance?
Dr S. Cobb/ Durham University
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The emergence of superbugs (MRSA)
1961: Emergence of bacterial
resistance to Methicillin
(Methicillin Resistant
Staphylococus aureus, MRSA)
Dr S. Cobb/ Durham University
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What is different about MRSA?
The enzyme that Methicillin targets is modified so that it can
no longer fit in the active site ( = no inhibition of enzyme).
Dr S. Cobb/ Durham University
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The emergence of superbugs (VRSA)
Normal peptide sequence in
vancomycin sensitive bacteria
Mutated peptide sequence in
Vancomycin resistant bacteria
Dr S. Cobb/ Durham University
19
Superbugs, is the situation really that bad?
No effective drugs left
Some drugs still
effective and more
Dr S. Cobb/
University
on Durham
the way
20
Superbugs, is the situation really that bad?
Lots of drugs
Dr S. Cobb/ Durham University
Not so many
21
Superbugs, is the situation really that bad?
Only three of
the approved
antibiotics in the
last 10 years
(25% of total)
have of new
mode of action
Dr S. Cobb/ Durham University
22
The next generation of antibiotics
Ideally any new antibiotic must have:
1. New mode of action so it can be used against MRSA etc
2. Non-toxic to human cells (magic bullet effect)
http://en.wikipedia.org/wiki/List_of_antibiotics
In my group we want to develop a new class of antibiotics
that are derived from our bodies own defence system to
infection, the innate immune response.
Dr S. Cobb/ Durham University
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Innate immunity
What happens when you cut your finger?
How does your body fight potential infection?
Dr S. Cobb/ Durham University
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Innate immunity
What happens when you cut your finger?
How does your body fight potential infection?
Innate immunity – fast,
brute force, no real plan,
not coordinated
Adaptive immunityantibodies, highly
effective, calculated
Dr S. Cobb/ Durham University
25
The innate immune response in action
The S. aureus bacteria
grows but your skin
releases a compound as
part of the innate immune
response that can kill the
E. coli bacteria.
Dr S. Cobb/ Durham University
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The innate immune response in action
Your skin releases a compound as part of innate immune
response that can kill E. Coli bacteria.
The compound is a peptide that is part of a range of
antimicrobial peptides that the body can produce as a
first line defence against infection.
Dr S. Cobb/ Durham University
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Antimicrobial peptides
Positively charged peptide molecules (charge typically
between +2 to +9).
They range in size from 12 to 100 amino acids in length.
Extremely potent (nM) against a broad spectrum of bacteria
including drug resistant strains (MRSA and VRSA) due to a
different mode of action.
Dr S. Cobb/ Durham University
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Antimicrobial peptides
Dr S. Cobb/ Durham University
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Antimicrobial peptides and their selectivity for bacteria
Dr S. Cobb/ Durham University
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Antimicrobial peptides and their mode of action
http://www.youtube.com/watch?v=9-HegAO4T0A
Dr S. Cobb/ Durham University
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Our research on antimicrobial peptides
Antibacterial Surfaces
New Drugs
Dr S. Cobb/ Durham University
32
Summary
Many of the antibiotics developed in the 1930s and 1940s
are no longer active against the bacteria that they were
designed to target.
New strains of superbugs have been emerging since the
1960s. At present MRSA is the main problem, but VRSA
represents a much bigger problem on the horizon.
At the present time we are winning the fight against bacteria,
but in the next 10 years…….
Dr S. Cobb/ Durham University
33
Antibiotics beyond 2011……
The NHS
The drug companies
The academics
The future………
Dr S. Cobb/ Durham University
34
I wonder how she’ll
react when I tell her
I need to got to the
toilet again!
This will keep
you safe from
that pesky
VRSA.
Going to school 2020?
Dr S. Cobb/ Durham University
35
The superbugs are
coming!
The race for new antibiotics
Any questions?
Dr Steven Cobb
Chemistry Department
Durham University
s.l.cobb@durham.ac.uk
Dr S. Cobb/ Durham University
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