Antiobiotic Resistance

Antibiotic Resistance

So You Think You Are Alone?Fall 2009

Long Interest in Controlling Pests

• Pests that eat our crops/livestock• Pests that compete with our crops• Pests that damage our materials• Pests that cause diseases in humans or our

plants and animals

Pesticides

• Chemicals used to kill pests

• “First generation” of chemical pesticides used to kill pests were sometimes effective, but often had bad side effects– Arsenic, cyanide

• Improvements in organic chemistry allowed scientists to develop “second generation” synthetic organic pesticides- 1940s

DDT dichlorodiphenyltrichloroethane

• Swiss scientist ,Muller, discovered an organic compound that killed insects– Relatively cheap to produce– Broad spectrum– Persistent

• “Silver Bullet” in the battle against pests.

DDT

• Used to fight body lice and other insect disease vectors (e.g. malaria mosquitos) in WW2 , very effective

• Used to control agricultural pests– Originally effective at

controlling pests

DDT

• Muller won the Nobel Prize for the discovery of DDT

Evolution of DDT resistance

Pesticide Treadmill

• As pests become resistant to pesticides farmers responded by increasing the concentration of pesticides which selects for more resistant pests so farmers increase the concentration of pesticides ……

• Over the last 50 years farmers increased the amount of pesticides added 40 fold and suffer s lightly larger loss of crops to pests.

Not just DDT

Evolution of Pesticide Resitance

Other Problems From Applying Chemical Pesticides to Control Crops

• Often saw unintended effects of applying pesticides– DDT affects calcium metabolism and thus

weakened bird shells– Sometimes killed beneficial insects• Those that act as competitors or predators of pests

Other Problems From Applying Chemical Pesticides to Control Crops

• Resurgence– Applying pesticides initially lowers pest population

initially lowers pest populations but later the pest populations explode to a much larger size than before• Probably occurs because the pesticide has killed a

competitor or a predator that controlled the pests population size

Other Problems From Applying Chemical Pesticides to Control Crops

• Secondary Outbreaks– Adding pesticides initially lowers the population of

the pest species – But over time the population of a second species

that wasn’t initially a problem becomes so large that the second species becomes a larger population than the first species

What have we learned from ecology and evolutionary biology?

• Adding pesticides often has unintended consequences

• Especially true when adding “broad spectrum” pesticides

• We might expect similar effects when taking antibiotics

What have we learned from ecology and evolutionary biology?

• Animals, plants, and microbes have evolved resistance to pesticides.

• What a surprise, Natural selection works!!!!

• Should also be a concern for antibiotics

AntibioticsAntibiotics, also known as antimicrobial drugs, are drugs that fight infections caused by bacteria.

From CDC

Antibiotics

• Alexander Fleming discovered the first antibiotic, penicillin, in 1927. After the first use of antibiotics in the 1940s, they transformed medical care and dramatically reduced illness and death from infectious diseases.

from CDC

Antibiotics

• About 150 antibiotics used in medicine today

How do antibiotics work?

• An antibiotic is a selective poison– kill the desired bacteria, but not the cells in your

body.

How Do Antibiotics Work

• Antibiotics are compounds that either:

– 1. kill bacteria directly (bacteriocidal)

– 2. hamper their ability to grow and reproduce (bacteriostatic)

How Do Antibiotics Work?

• When you are fighting off a bacterial infection, your immune system can be overwhelmed by the invading bacteria.

– Antibiotics help fight the invaders until your immune system can recover and finish off the remaining bacteria.

How do antibiotics work?

Mechanisms• crippling production of the bacterial cell wall that

protects the cell from the external environment • interfering with protein synthesis by binding to

the machinery that builds proteins• Disrupting with metabolic processes, such as the

synthesis of folic acid, a B vitamin that bacteria need to thrive

• blocking synthesis of DNA and RNA

Antibiotic Target Site or mode of action

Penicillin Gram-positive bacteria Wall synthesis Cephalosporin Broad spectrum Wall synthesis Griseofulvin Dermatophytic fungi Microtubules Bacitracin Gram-positive bacteria Wall synthesis Polymyxin B Gram-negative bacteria Cell membrane Amphotericin B Fungi Cell membrane Erythromycin Gram-positive bacteria Protein synthesis Neomycin Broad spectrum Protein synthesis Streptomycin Gram-negative bacteria Protein synthesis Tetracycline Broad spectrum Protein synthesis Vancomycin Gram-positive bacteria Protein synthesis Rifamycin Tuberculosis Protein synthesis Gentamicin Broad spectrum Protein synthesis

Antibiotics Save The Day!!!!!!

But…….

Antibiotic Resistance

Q: What is antibiotic resistance?

A: Antibiotic resistance is the ability of bacteria or other microbes to resist the effects of an antibiotic. Antibiotic resistance occurs when bacteria change in some way that reduces or eliminates the effectiveness of drugs, chemicals, or other agents designed to cure or prevent infections. The bacteria survive and continue to multiply causing more harm.

From- CDC

Antibiotic Resistance

Antibiotic Resistance

• Neisseria gonorrhoeae is the bacteria that causes gonorrhea

• In the 1960s penicillin and ampicillin were able to control most cases of gonorrhea. – Today, more than 24 percent

of gonorrheal bacteria in the U.S. are resistant to at least one antibiotic

– 98 percent of gonorrheal bacteria in Southeast Asia are resistant to penicillin

Selection for Antibiotic Resistance

Antibiotic Resistance and Pesticide Resistance Arise by Natural Selection (notice how the term “natural selection” doesn’t appear in the CDC

definition)

why???????

CoevolutionEvolutionary Arms Race

Red Queen

Microbes Evolve Quickly

1.Short generation times2.Large populations3.Lateral transmission of genes

6 Scariest GermsInfectious Diseases Society of America

Staphylococcus aureus

• First bacterium to show resistance to penicillin- 1947– Just four years after the drug was mass produced

• Methicillin was antibiotic of choice, but damaged kidney so replaced by oxacillin

• MRSA (methicillin-resistant Staphylococcus aureus) was first detected in Britain in 1961– Now common in hospitals– Most common antibiotic resistant microbe in US hospitals.

• Half of all S. aureus infections in the USA are resistant to penicillin, methicillin, tetracyclind and erythromycin.

MRSA

• Drug-resistant "staph" causes 102,000 hospital infections a year, more than any other.

• For sick patients, it can be a killer.

• Recently, S. aureus has escaped the hospital.

• The number of children infected jumped 28% in three years.

MRSA and Artificial Turf

• MRSA found in artificial turf.• At least 276 football players

were infected with MRSA from 2003 through 2005– 517 for each 100,000,– 32 in 100,000 in regular

population• Football players often become

infected at the site of a turf burn and are misdiagnosed

• 2003, 5 St. Louis Rams contracted MRSA

SAFE

NOT SAFE

Escheria coli and Klebsiella

• These bacteria, a major cause of urinary tract, gastrointestinal and wound infections, are quickly becoming resistant to existing drugs.

• Half of Klebsiella, for instance, were found to be resistant to Cipro in a recent study.

• More worrisome, two experimental drugs being tested against these bacteria are in the same class as drugs to which the bugs are already resistant.

Acinetobacter baumannii

• This bacteria is perhaps most well known for its presence in troops returning from Iraq, where it has infected dozens of patients and spread to others inside hospitals.

• It is also an increasingly common cause of pneumonia, now accounting for 7% of hospital-acquired cases.

• There are few existing drugs to treat it, and no medicines in development targeted at this bacteria.

Aspergillis

• Cancer patients, transplant patients and others with weak immune systems are at risk of being infected with this fungus.

• Once it gets loose in the bloodstream, aspergillis kills 50% of the time or more--and that's with the best new antifungal drugs that have been developed in recent years.

• Experts complain that drug companies are choosing to test their medicines on other, easier-to-treat fungal infections.

Vancomycin-resistant Enterococcus faecium (VRE)

• VRE is a major cause of infection of the heart, brain and the abdomen.

• A recent survey of 494 U.S. hospitals found infections of 10% across all patient groups.

• Current drugs do not rapidly kill the bacteria, and only one is available as a pill.

Pseudomonas aeruginosa

• This bug is better than most other bacteria at becoming resistant to new antibiotics.

• A third of P. aeruginosa were found to be resistant to drugs like Cipro and Levaquin in 2002.

• Patients with cystic fibrosis are at particular risk; antibiotics can keep them healthy, but once bacteria become resistant, they may need lung transplants.

Michaelis sanfranciscoii

• Resistant to all know types of student (and faculty) complaints

• Puts students in near death catatonic state with persistently boring lectures

• Capable of psychologically scarring eager young scholars with capricious and arbitrary grading style

How did this happen?

• Plenty of blame to go around– Doctors– Patients– Livestock industry

How did this happen?

• Antibiotics are effective against bacteria and NOT viruses– Many physicians have prescribed antibiotics to

treat viral diseases such as the common cold– Provided selection for resistance while providing

no health benefit

(maybe they should have taught about Natural Selection in Medical School)

How did this happen?

• Patients don’t take all of their medicine– If they stop taking their medicine after they feel better the

only bacteria left in their bodies are the ones that are resistant

• Demand a prescription even when not appropriate

(maybe potential patients should learn about natural selection in school)

How did this happen?• Feed antibiotics to livestock

– Increase the growth rate, therefore increase meat production

• 9 – 13 million Kg fed to livestock each year in the USA• Supplies a continuous selective pressure

• (maybe livestock producers, or the people who regulate them, should learn about natural selection)

Potential Unintended Consequences

• Antibiotics deposited in manure

• Manure is often used to fertilize crops

• Antibiotics end up in the soil– May alter soil

microbial community

Where do we find antibiotics?

• Because organisms have been in evolutionary arms races against microbes for such a long time it is not surprising that many antibiotics are natural chemicals

Where do we find antibiotics?

Natural products – A number of natural products, penicillin for

example, have been discovered that are antibiotics suitable for therapy.

– They were originally discovered as secretions of fungi or soil bacteria• Now found in tropical rainforest plants and coral reef

animals and plants

Finding New Natural Antibiotics

• Bioprospecting– Searching for natural chemicals with antiobiotic

properties• Two approaches to bioprospecting– Test everything to see if you can find any natural

chemicals with antibiotic ability– Focus on species used by traditional medicine• Rely on indigenous knowledge

Rely on Traditional Knowledge

Traditional Knowledge

• Rosy Periwinkle– Madagascar• Diabetes• Anti cancer

• Neem tree (Azadirachta indica)– India– antifungal

Bioprospecting

Bioprospecting vs Biopiracy

• Many antibiotics have been found in tropical rainforests and coral reefs– “value” to the biodiversity – If local people can make money from drugs

developed out of local ecosystems they might be more interested in conserving habitats and diversity

• “Biopiracy” occurs when big corporations take drugs from tropical ecosystem and make a fortune, but return no money to the local community.

Fighting “Biopiracy”

• Many tropical countries have made it much more difficult for scientists to remove material from the country– Can make it harder for scientists to do their

research– E.g. difficult to remove materials from Malaysia• Even tissues from the wings of bats that could be used

in genetic analysis

Where do we find antibiotics?

• Semi-synthetic products. These are natural products that have been chemically modified in the laboratory to – improve the efficacy of the natural product – reduce its side effects – circumvent developing resistance by the targeted

bacteria – expand the range of bacteria that can be treated with

it

Where do we find antibiotics?

• Completely synthetic products.– Create new chemicals in the lab– Fluoroquinolones• broad-spectrum antibiotics • Cipro

If microbes are resistant to antibiotics then we should develop new types of antibiotics.

New Antibiotics

• In the past decade, many big pharmaceutical players, including Wyeth, Roche and Eli Lilly, backed off antibiotic research.

• At the same time, new antibiotics were becoming increasingly difficult to develop.

• For 30 years--until 2000--there were no new classes of antibiotics approved.

New Antibiotics

• In the past six years, there have been some new types of drugs– Zyvox, from Pfizer – Cubicin, from Cubist Pharmaceuticals And maybe• Tygacil from Wyeth• Ketek from Sanofi-Aventis

Microbiological vs Evolutionary Knowledge

• Lots of progress has been made by scientists with detailed knowledge of how bacteria work

• However, organisms have been involved in evolutionary arms race with microbes for very long time – we might be able to learn something from our

knowledge of evolutionary biology

How Can We Use Our Knowledge of Evolutionary Biology?

• Don’t use antibiotics to treat viral infections.

Antibiotics kill bacteria, not viruses. If you take antibiotics for a viral infection (like a cold or the flu), you will not kill the viruses, but you will introduce a selective pressure on bacteria in your body, inadvertently selecting for antibiotic-resistant bacteria.

• Basically, you want your bacteria to be “antibiotic virgins,” so that if they someday get out of hand and cause an infection that your immune system can’t handle, they can be killed by a readily available antibiotic.

UC Berkeley

How Can We Use Our Knowledge of Evolutionary Biology?

• Avoid mild doses of antibiotics over long time periods.•

If an infection needs to be controlled with antibiotics, a short-term, high-dosage prescription is preferable. This is because you want to kill all of the illness-causing bacteria, leaving no bacterial survivors.

• Any bacteria that survive a mild dose are likely to be somewhat resistant. Basically, if you are going to introduce a selective pressure (antibiotics), make it so strong that you cause the extinction of the illness-causing bacteria in the host and not their evolution into resistant forms.

How Can We Use Our Knowledge of Evolutionary Biology?

• When treating a bacterial infection with antibiotics, take all your pills.

Just as mild doses can breed resistance, an incomplete regimen of antibiotics can let bacteria survive and adapt. If you are going to introduce a selective pressure (antibiotics), make it a really strong one and a long enough one to cause the extinction of the illness-causing bacteria and not their evolution.

How Can We Use Our Knowledge of Evolutionary Biology?

• Use a combination of drugs to treat a bacterial infection.

If one particular drug doesn’t help with a bacterial infection, you may be dealing with a resistant strain. Giving a stronger dose of the same antibiotic just increases the strength of the same selective pressure—and may even cause the evolution of a “super-resistant” strain.

• Instead, you might want to try an entirely different antibiotic that the bacteria have never encountered before. This new and different selective pressure might do a better job of causing their extinction, not their evolution.

How Can We Use Our Knowledge of Evolutionary Biology?

• Reduce or eliminate the “preventive” use of antibiotics on livestock and crops.

• Unnecessary use of antibiotics for agricultural and livestock purposes may lead to the evolution of resistant strains. Later, these strains will not be able to be controlled by antibiotics when it really is necessary.

• Preventive use of antibiotics on livestock and crops can also introduce antibiotics into the bodies of the humans who eat them.

How Can We Use Our Knowledge of Evolutionary Biology?

• We discussed how a benefit of sexual reproduction is the ability to fight infectious microbes by scrambling our genotypes (hence our defenses)

• Maybe we can use this knowledge of the importance of varying our defenses over time to help us fight microbes

HIV

1. What are the evolutionary origins of HIV?

• HIV is closely related to other viruses. – SIVs (simian immunodeficiency viruses)• infect primates

– HIV more distantly related to FIVs (the feline strains), which infect cats.

Origin of HIV

• Chimpanzees in West Africa are the source of HIV infection in humans. – The virus most likely jumped to humans when

humans hunted these chimpanzees for meat (bushmeat) and came into contact with their infected blood

HIV

• Interestingly related viral lineages showed that primates with SIV and wild cats with FIV don't seem to be harmed by the viruses they carry.

• If scientists can figure out how non-human primates and wild cats are able to live with these viruses, they may learn how to better treat HIV infections or prevent them altogether.

Ways to Fight HIV• Reverse transcriptase (RT) inhibitors interfere with the critical step

during the HIV life cycle known as reverse transcription. During this step, RT, an HIV enzyme, converts HIV RNA to HIV DNA. There are two main types of RT inhibitors.

• Protease inhibitors interfere with the protease enzyme that HIV uses to produce infectious viral particles.

• Entry and fusion inhibitors interfere with the virus' ability to fuse with the cellular membrane, thereby blocking entry into the host cell.

• Integrase inhibitors block integrase, the enzyme HIV uses to integrate genetic material of the virus into its target host cell.

• Multidrug combination products combine drugs from more than one class into a single product.

How can we control HIV's evolution of resistance to our drugs?

Because of HIV's speedy evolution, it responds to selection pressures quickly: viruses that happen to survive the drug are favored, and resistant virus strains evolve within the patient, sometimes in just a few weeks.

AIDS Cocktail

AIDS Cocktail

AIDS Cocktail

• HIV treated a “cocktail” that contains three different drugs and thus tries to stop the virus in three different ways.

• Three-drug cocktail