The evolution of antibiotic resistance

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The evolution ofantibiotic resistance

• Rob Knell / Lars Chittka

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MRSA in the UK
Deaths per year
Source Health Protection Agency
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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

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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 gt60,000, whereas non-resistant TB
  costs about 6,000 to treat

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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
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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/educational/penicil
  lin/readmore.html

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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.

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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
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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

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Mechanisms of resistance
Imipenem resistant Pseudomonas aeruginosae
Streptococcus pneumoniae resistance to penicillins
Tetracycline
MRSA penicillin binding protein PBP2A
Penicillins, Cephalosporins
Hawkey, P. M BMJ 1998317657-660
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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

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Horizontal transfer

• Simple selection isnt 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

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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

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Managing resistance

• There are two different approaches to managing
  antibiotic resistance
• Managing existing resistant pathogens
• 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

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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?

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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