The evolution of
antibiotic resistance
Rob Knell / Lars Chittka
MRSA in the UK
Deaths
per
year
Source: Health Protection Agency
MRSA - Methicillin resistant
Staphylococcus aureus
-S. aureus is a common bacterium that
can be found on the skin of many healthy
people
-it typically causes only minor infections (in
“pimples” but can also cause serious
diseases (e.g. pneumonia))
-First report of resistance to penicillin in 1947
-MRSA is also resistant to ampicillin and other
penicillins, erythromycin, tetracycline
-can only be treated with Vancomycin
-Vancomycin-resistant strains have
already been found and bred
Examples of resistant
bacteria
•Mycobacterium tuberculosis: causes TB
• Originally controlled with Streptomycin
• Now often resistant to a variety of antibiotics
• The frequency of multi-drug resistant TB in
the late 1990s was 1.2% in the UK
• Multi-drug resistant TB requires the patient
to be given a two-year course of therapy
• This costs >£60,000, whereas non-resistant
TB costs about £6,000 to treat
What are antibiotics?
• Have been used by fungi to kill
bacteria for many millions of years
• First discovered in 1929 by A.
Fleming
• Brought into widespread use in the
1940s
• Antibiotics are chemicals that kill
bacteria
• Their introduction was arguably the
biggest medical breakthrough since
sanitation
Penicillin
A discovery by
accident
• A fungal spore that the wind might
have blown into his lab while Fleming
was on vacation in 1928, forever
changed the course of medicine...
• A. Fleming named the substance
Penicillin, after the mould Penicillium
notatum – but was unable to isolate the
substance
• In the late 1930s and early 1940s, E.
Chain & H. Florey managed to produce
larger amounts of penecillin, and ran
successful trials on mice
• Nobel prize in 1945
• http://nobelprize.org/medicine/educatio
nal/penicillin/readmore.html
Antibiotic use and
misuse
•During the 1940s and 1950s antibiotics were
extremely effective
•They were (and still are) widely prescribed, often
for medical conditions that did not require them
•Antibiotics started to be used in agriculture:
dosing cattle with antibiotics increases yield, and
battery farming relies on antibiotics to control
infection
•By the 1970s the World was awash with
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 early as 1946, scientists (including A. Fleming)
were warning of the possible dangers of
antibiotic-resistant bacteria
•A few bacteria in populations that have never
been exposed to artificial antibiotics probably
carry alleles that give resistance to antibiotics
•Resistance alleles can also arise by mutation
•Resistant bacteria can use a number of
mechanisms to overcome antibiotics
Mechanisms of
resistance Imipenem resistant
Pseudomonas
aeruginosae
Streptococcus
pneumoniae
resistance to
penicillins
Tetracycline
MRSA penicillin
binding protein
PBP2A
Penicillins,
Cephalosporins
Hawkey, P. M BMJ 1998;317:657-660
Evolution of resistance
•Antibiotic use represents a strong selection
pressure
•If a population of bacteria with a few resistant
individuals is exposed to a lethal antibiotic, the
susceptible bacteria will die, but the resistant
bacteria will survive
•In an environment with a lot of antibiotic use,
resistance alleles spread rapidly
•The problem is compounded by horizontal gene
transfer and by cross-resistance
Horizontal transfer
•Simple selection isn’t the only means for
resistance alleles to spread
•Bacteria can acquire resistance genes by
transformation, when they pick up DNA from the
environment
•They can also get resistance genes by
conjugation: bacterial sex, when they exchange
plasmids
•Plasmids can have multiple resistance genes,
conferring multiresistance
Cross-resistance
•Resistance to one antibiotic can confer resistance
to others
•Resistance to cephalosporins gives resistance to
methicillin, even in bacteria that have never been
exposed to methicillin
Managing resistance
•There are two different approaches to managing
antibiotic resistance:
1.Managing existing resistant pathogens
2.Avoiding future evolution of more resistance
•The first can be done by, in the case of MRSA,
improving hygiene in hospitals, screening hospital
visitors and isolating patients
•The second can be done by changing selection
on bacteria
Selection and
resistance
•Reduce inappropriate prescription of antibiotics
• Increase public awareness that many
diseases cannot be cured with antibiotics
•Reduce use of agricultural antibiotics
•Increase the number of patients who finish their
courses of antibiotics
•Restrict the use of new antibiotics
•Where possible, use other treatments:
• Vaccines
• Phage treatment?
Mechanisms of
resistance
• 1. Antibiotic modification: some bacteria have enzymes
that cleave or modify antibiotics: e.g. b lactamase
inactivates penicillin
• 2. Denied access: membrane becomes impermeable for
antibiotic: e.g. imipenem
• 3. Pumping out the antibiotic faster than it gets in: e.g.
tetracyclines
• 4. Altered target site: antibiotic cannot bind to its intended
target because the target itself has been modified
• 5. production of alternative target (typically enzyme): e.g.
Alternative penicillin binding protein (PBP2a) in MRSA