The evolution ofantibiotic resistance

The evolution of
antibiotic resistance
Rob Knell / Lars Chittka
MRSA in the UK
Source: Health Protection Agency
Deaths
per
year
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/educational/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
Hawkey, P. M BMJ 1998;317:657-660
Penicillins,
Cephalosporins
Tetracycline
Streptococcus pneumoniae resistance to penicillins
MRSA penicillin binding protein PBP2A
Imipenem resistant Pseudomonas aeruginosae
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:
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
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