The evolution of

antibiotic
resistance
Rob Knell / Lars Chittka
Rob Knell / Lars Chittka
 MRSA in the UK

Deaths
per
year

Source: Health Protection Agency

 MRSA
MRSA -- Methicillin
Methicillin resistant
resistant
-S. aureus is a common bacterium that
Staphylococcus
Staphylococcus aureus
aureus
can-S.be foundison
aureus a the skin of
common many healthy
bacterium that
people
can be found on the skin of many healthy
people
-it typically causes only minor infections (in
“pimples” butcauses
-it typically can also cause
only minorserious
infections (in
diseases (e.g.but
“pimples” pneumonia))
can also cause serious
diseases (e.g. pneumonia))
-First report of resistance to penicillin in 1947
-First report of resistance to penicillin in 1947
-MRSA is also resistant to ampicillin and other
penicillins, erythromycin,
-MRSA is also resistant totetracycline
ampicillin and other
penicillins, erythromycin, tetracycline
-can only be treated with Vancomycin
-can only be treated with Vancomycin
-Vancomycin-resistant strains have
already been found and bred
-Vancomycin-resistant strains have
already been found and bred
 Examples of resistant
bacteria
••Mycobacterium
Mycobacterium tuberculosis:
tuberculosis: causes
causes TB
TB
•• Originally
Originally controlled
controlled with
with Streptomycin
Streptomycin
•• Now
Now often
often resistant
resistant to
to aa variety
variety of
of
antibiotics
antibiotics
•• The
The frequency
frequency of of multi-drug
multi-drug resistant
resistant TB
TB
in
in the
the late
late 1990s
1990s was
was 1.2%
1.2% inin the
the UK
UK
•• Multi-drug
Multi-drug resistant
resistant TB
TB requires
requires the
the
patient
patient toto be
be given
given aa two-year
two-year course
course of
of
therapy
therapy
•• This
This costs
costs >£60,000,
>£60,000, whereas
whereas non-
non-
resistant
resistant TBTB costs
costs about
about £6,000
£6,000 toto treat
treat
 What are
antibiotics?
••Have
Have been
been used
used by
by fungi
fungi to
to kill
kill
bacteria
bacteria for
for many
many millions
millions of
of
years
years
••First
First discovered
discovered inin 1929
1929 by
by A.
A.
Fleming
Fleming
••Brought
Brought into
into widespread
widespread useuse
in
in the
the 1940s
1940s Penicillin
••Antibiotics
Antibiotics are
are chemicals
chemicals that
that
kill
kill bacteria
bacteria
••Their
Their introduction
introduction was
was
arguably
arguably thethe biggest
biggest medical
medical
breakthrough
breakthrough since
since sanitation
sanitation
A discovery by
accident
••AA fungal
fungal spore
spore that
that the
the wind
wind might
might
have
have blown
blown into
into his
his lab
lab while
while Fleming
Fleming

 
was
was on on vacation
vacation inin 1928,
1928, forever
forever
changed
changed the the course
course of of medicine...
medicine...
••A.
A. Fleming
Fleming named
named the the substance
substance
Penicillin,
Penicillin, after
after the
the mould
mould Penicillium
Penicillium
notatum
notatum –– but but was
was unable
unable to to isolate
isolate
                                                     

the
the substance
substance
••InIn the
the late
late 1930s
1930s and
and early
early 1940s,
1940s, E.
E.
Chain
Chain & & H.
H. Florey
Florey managed
managed to to
produce
produce larger
larger amounts
amounts of of penecillin,
penecillin,
and
and ranran successful
successful trials
trials on
on mice
mice
••Nobel
Nobel prize
prize in
in 1945
1945
••http://nobelprize.org/medicine/educat
http://nobelprize.org/medicine/educat
ional/penicillin/readmore.html
ional/penicillin/readmore.html
 Antibiotic use and
misuse
••During
During the
the 1940s
1940s and
and 1950s
1950s antibiotics
antibiotics
were
were extremely
extremely effective
effective
••They
They were
were (and
(and still
still are)
are) widely
widely prescribed,
prescribed,
often
often for
for medical
medical conditions
conditions that
that did
did not
not
require
require them
them
••Antibiotics
Antibiotics started
started to to be
be used
used inin agriculture:
agriculture:
dosing
dosing cattle
cattle with
with antibiotics
antibiotics increases
increases yield,
yield,
and
and battery
battery farming
farming relies
relies on
on antibiotics
antibiotics to
to
control
control infection
infection
••By
By the
the 1970s
1970s the
the World
World waswas awash
awash with
with
antibiotics.
antibiotics.
 Antibiotic use and
misuse
"There was complacency in the 1980s. The perception was that
we had licked the bacterial infection problem. Drug companies
weren't working on new agents. They were concentrating on
other areas, such as viral infections. In the meantime, resistance
increased to a number of commonly used antibiotics, possibly
related to overuse of antibiotics. In the 1990s, we've come to a
point for certain infections that we don't have agents available."

Michael Blum, M.D., medical officer in the Food and Drug

Administration's division of anti-infective drug products. Quoted
in Lewis, R. (1995)The Rise of Antibiotic-Resistant Infections.
Available online at
http://www.fda.gov/fdac/features/795_antibio.html
 Resistance
••As
As early
early as
as 1946,
1946, scientists
scientists (including
(including A.
A.
Fleming)
Fleming) were
were warning
warning of of the
the possible
possible
dangers
dangers ofof antibiotic-resistant
antibiotic-resistant bacteria
bacteria
••AA few
few bacteria
bacteria inin populations
populations that
that have
have
never
never been
been exposed
exposed to to artificial
artificial antibiotics
antibiotics
probably
probably carry
carry alleles
alleles that
that give
give resistance
resistance to
to
antibiotics
antibiotics
••Resistance
Resistance alleles
alleles can
can also
also arise
arise by
by
mutation
mutation
••Resistant
Resistant bacteria
bacteria can
can use
use aa number
number of of
mechanisms
mechanisms to to overcome
overcome antibiotics
antibiotics
 Mechanisms of
resistance Imipenem resistan
Pseudomonas
aeruginosae
Streptococcu
s
pneumoniae Tetracycline
resistance to
penicillins

MRSA
penicillin Penicillins,
binding Cephalospori
protein ns
PBP2A
Hawkey, P. M BMJ 1998;317:657-660
 Evolution of
resistance
•Antibiotic
Antibiotic use
use represents
represents aa strong
strong selection
selection
pressure
pressure
•IfIf aa population
population of of bacteria
bacteria with
with aa few
few
resistant
resistant individuals
individuals is
is exposed
exposed to to aa lethal
lethal
antibiotic,
antibiotic, the the susceptible
susceptible bacteria
bacteria will
will die,
die,
but
but thethe resistant
resistant bacteria
bacteria will
will survive
survive
•In
In anan environment
environment withwith aa lot
lot of
of antibiotic
antibiotic
use,
use, resistance
resistance alleles
alleles spread
spread rapidly
rapidly
•The
The problem
problem isis compounded
compounded by by horizontal
horizontal
gene
gene transfer
transfer and
and by
by cross-resistance
cross-resistance
 Horizontal transfer
•Simple
Simple selection
selection isn’t
isn’t the
the only
only means
means for
for
resistance
resistance alleles
alleles to
to spread
spread
•Bacteria
Bacteria can
can acquire
acquire resistance
resistance genes
genes by
by
transformation,
transformation, when
when they
they pick
pick up
up DNA
DNA
from
from the
the environment
environment
•They
They can
can also
also get
get resistance
resistance genes
genes by
by
conjugation:
conjugation: bacterial
bacterial sex,
sex, when
when they
they
exchange
exchange plasmids
plasmids
•Plasmids
Plasmids can
can have
have multiple
multiple resistance
resistance
genes,
genes, conferring
conferring multiresistance
multiresistance
 Cross-resistance
•Resistance
Resistance to
to one
one antibiotic
antibiotic can
can confer
confer
resistance
resistance to
to others
others
•Resistance
Resistance to
to cephalosporins
cephalosporins gives
gives
resistance
resistance to
to methicillin,
methicillin, even
even in
in bacteria
bacteria
that
that have
have never
never been
been exposed
exposed toto methicillin
methicillin
 Managing
resistance
••There
There are
are two
two different
different approaches
approaches to
to
managing
managing antibiotic
antibiotic resistance:
resistance:
1.Managing
1. Managing existing
existing resistant
resistant pathogens
pathogens
2.Avoiding
2. Avoiding future
future evolution
evolution of of more
more
resistance
resistance
••The
The first
first can
can be
be done
done by,by, in
in the
the case
case of
of
MRSA,
MRSA, improving
improving hygiene
hygiene in in hospitals,
hospitals,
screening
screening hospital
hospital visitors
visitors and
and isolating
isolating
patients
patients
••The
The second
second can
can be
be done
done by
by changing
changing
selection
selection onon bacteria
bacteria
 Selection and
resistance
••Reduce
Reduce inappropriate
inappropriate prescription
prescription of
of
antibiotics
antibiotics
•• Increase
Increase public
public awareness
awareness that
that many
many
diseases
diseases cannot
cannot bebe cured
cured with
with antibiotics
antibiotics
••Reduce
Reduce useuse of
of agricultural
agricultural antibiotics
antibiotics
••Increase
Increase the
the number
number of of patients
patients who
who finish
finish
their
their courses
courses of
of antibiotics
antibiotics
••Restrict
Restrict the
the use
use of
of new
new antibiotics
antibiotics
••Where
Where possible,
possible, use
use other
other treatments:
treatments:
•• Vaccines
Vaccines
•• Phage
Phage treatment?
treatment?
 Mechanisms of
resistance
••1.
1. Antibiotic
Antibiotic modification:
modification: some
some bacteria
bacteria have
have
enzymes
enzymes that
that cleave
cleave oror modify
modify antibiotics: e.g. 
antibiotics: e.g.
lactamase
lactamase inactivates
inactivates penicillin
penicillin
••2.
2. Denied
Denied access:
access: membrane
membrane becomes
becomes impermeable
impermeable
for
for antibiotic:
antibiotic: e.g.
e.g. imipenem
imipenem
••3.
3. Pumping
Pumping out out the
the antibiotic
antibiotic faster
faster than
than itit gets
gets in:
in:
e.g.
e.g. tetracyclines
tetracyclines
••4.
4. Altered
Altered target
target site:
site: antibiotic
antibiotic cannot
cannot bind
bind toto its
its
intended
intended target
target because
because the
the target
target itself
itself has
has been
been
modified
modified
••5.
5. production
production of of alternative
alternative target
target (typically
(typically
enzyme):
enzyme): e.g.
e.g. Alternative
Alternative penicillin
penicillin binding
binding protein
protein
(PBP2a)
(PBP2a) inin MRSA
MRSA