Development of resistant Staphylococcus aureus over time

Development of antibiotic resistant Staphylococcus aureus over time

Attacks and Defenses CourseUniversity of Vermont College of Medicine

January 2011

Timothy Plante, MS-IV

AboutThis is a presentation that I made my senior year in medical school for an infectious disease course at the University of Vermont College of Medicine. It was picked up by BoingBoing.net and was viewed by quite a few folks on the internet.

AboutThis is a presentation that I made my senior year in medical school for an infectious disease course at the University of Vermont College of Medicine. It was picked up by BoingBoing.net and was viewed by quite a few folks on the internet.

I had a lot of fun making this. Enjoy!

Once upon a time there was a bacterium. All of his bacteria friends thought he was pretty good looking.

Once upon a time there was a bacterium. All of his bacteria friends thought he was pretty good looking.

They would comment on how nice his gold color was.

Once upon a time there was a bacterium. All of his bacteria friends thought he was pretty good looking.

Once upon a time there was a bacterium. All of his bacteria friends thought he was pretty good looking.

And because of that, he was named staph aureus as auro is the Latin word for gold.

They would comment on how nice his gold color was.

Here’s staph aureus’ nice thick peptidoglycan wall!

membrane

Peptidoglycan layer

Here he is in his towel returning from the Gram Stain water park! His peptidoglycan layer got darkly stained.

Look! He’s all purple! That’s why he’s called gram positive.

Here he is in his towel returning from the Gram Stain water park! His peptidoglycan layer got darkly stained.

Staph aureus likes to live on your body with his friends. The best way is in clusters!

Skin!

In your nares!

He has a kitty named Catalase.

Catalase is a little strange

as she only eats hydrogen peroxide

H2O2

H2O2

and only pees out H2O and O2.

H2O2

H2O2

H2O2

H2O2

H2O2

H2O2

H2O2

H2O2

H2O2

H2O2

H2O2

H2O2O2

H2O2

O2

Good kitty.

One day, staph aureus went for a hike and came across some fungus. It was called Penicillum.

As he got close, he started feeling funny.

Lets find out why…

membrane

Peptidoglycan layer

O COOH

R

membrane

Peptidoglycan layer

O COOH

R

Penicillin!

Transpeptidase(penicillin binding protein)

membrane

Peptidoglycan layer

O COOH

R

Penicillin!

membrane

Peptidoglycan layer

O COOH

R

Penicillin!

membrane

Peptidoglycan layer

O COOH

R

Penicillin!

membrane

Peptidoglycan layer

O COOH

R

Penicillin!

membrane

O COOH

R

Penicillin!

And then he died.

But for other staph aureus bacteria, this wasn’t much of a problem because they didn’t run into penicillium when they were hanging out in the skin or nares. They had a pretty fun life!

Sometimes they had a little too much fun and would cause infections

Like crusty superficial infections of the skin in kids called impetigo

Sometimes they would hang out in food and release cytolytic toxins that make people sick.

Food

Or would sneak into places where they shouldn’t by breaking down a component of collagen and the extracellular matrix, hyaluronic acid, with hyaluronidase!

hyal

uron

idas

e

Or would sneak into places where they shouldn’t by breaking down a component of collagen and the extracellular matrix, hyaluronic acid, with hyaluronidase!

hyal

uron

idas

e

Or would sneak into places where they shouldn’t by breaking down a component of collagen and the extracellular matrix, hyaluronic acid, with hyaluronidase!

hyal

uron

idas

e

Or would sneak into places where they shouldn’t by breaking down a component of collagen and the extracellular matrix, hyaluronic acid, with hyaluronidase!

hyal

uron

idas

e

Or would sneak into places where they shouldn’t by breaking down a component of collagen and the extracellular matrix, hyaluronic acid, with hyaluronidase!

hyal

uron

idas

e

Or would sneak into places where they shouldn’t by breaking down a component of collagen and the extracellular matrix, hyaluronic acid, with hyaluronidase!

hyal

uron

idas

e

Or would sneak into places where they shouldn’t by breaking down a component of collagen and the extracellular matrix, hyaluronic acid, with hyaluronidase!

Or would sneak into places where they shouldn’t by breaking down a component of collagen and the extracellular matrix, hyaluronic acid, with hyaluronidase!

Or would sneak into places where they shouldn’t by breaking down a component of collagen and the extracellular matrix, hyaluronic acid, with hyaluronidase!

Or would sneak into places where they shouldn’t by breaking down a component of collagen and the extracellular matrix, hyaluronic acid, with hyaluronidase!

Or would sneak into places where they shouldn’t by breaking down a component of collagen and the extracellular matrix, hyaluronic acid, with hyaluronidase!

Or would sneak into places where they shouldn’t by breaking down a component of collagen and the extracellular matrix, hyaluronic acid, with hyaluronidase!

Or would sneak into places where they shouldn’t by breaking down a component of collagen and the extracellular matrix, hyaluronic acid, with hyaluronidase!

He was very good at hide and seek whenever red blood cells were around.

He’d just release coagulase and they form a clot around him

And with just a little staphylokinase, the clot would break up!

And then just for fun, he’d blow up the red blood cells.

And then just for fun, he’d blow up the red blood cells.

And then just for fun, he’d blow up the red blood cells.

And then just for fun, he’d blow up the red blood cells.

Researchers one day would find that he and his friends strep pyogenes and strep agalactidae did this so well on a blood agar plate that they would be able to be identified by their complete hemolysis, a pattern we call beta hemolysis!

Beta’s the best!

Researchers one day would find that he and his friends strep pyogenes and strep agalactidae did this so well on a blood agar plate that they would be able to be identified by their complete hemolysis, a pattern we call beta hemolysis!

Every once and a while a white blood cell would try to pick on him

And would try to eat himA

But he’d prevent being phagocytosedA

With his nice polysaccharide slime layer and protein-A on his surface.

A

Then he’d blow up the white blood cell with leukocidin!

Leukocidin

Leukocidin

Then he’d blow up the white blood cell with leukocidin!

Leukocidin

Then he’d blow up the white blood cell with leukocidin!

Leukocidin

Then he’d blow up the white blood cell with leukocidin!

Then he’d blow up the white blood cell with leukocidin!

Leukocidin

Then he’d blow up the white blood cell with leukocidin!

TSS

When he was feeling really mean, he’d release a superantigen toxin

TSS

TS

S

When he was feeling really mean, he’d release a superantigen toxin

TSS

Like TSS-1 and cause toxic shock syndrome!

TS

S

When he was feeling really mean, he’d release a superantigen toxin

TSS

Like TSS-1 and cause toxic shock syndrome!

All of the lymphocytes would cause inflammation even though TSS-1 isn’t the antigen they’re supposed to react to!

TS

S

When he was feeling really mean, he’d release a superantigen toxin

TSS

Like TSS-1 and cause toxic shock syndrome!

All of the lymphocytes would cause inflammation even though TSS-1 isn’t the antigen they’re supposed to react to!

TS

S

When he was feeling really mean, he’d release a superantigen toxin

TSS

And people would get fever, low blood pressure, and a blanching rash that looked like a sunburn!

Like TSS-1 and cause toxic shock syndrome!

All of the lymphocytes would cause inflammation even though TSS-1 isn’t the antigen they’re supposed to react to!

But all in all, as long as he stayed away from the Penicillum fungus, there wasn’t too much to worry about!

Until one day when he was innocently hanging out in a joint having a bit of fun…

Until one day when he was innocently hanging out in a joint having a bit of fun…When he started feeling funny.

And he died.

But not just him! His friend causing endocarditis died!

And his friend causing cellulitis died!

And his friends causing impetigo died!

How could this be?

Penicillin!

How could this be?

Penicillin!

How could this be?

It seems someone figured out how to extract the active compound from the penicillum fungus and make it to a drug!

O COOH

R

So now staph aureus was dying left and right! Anytime they got out of control, they were taken down with some penicillin.

Until one day...

Until one day...

Until one day…One staph aureus didn’t seem bothered by the penicillin!

Let’s see why…

membrane

Peptidoglycan layer

Well those are new! What do they do?

membrane

Peptidoglycan layer

O

Uh oh, here comes Penicillin!

membrane

Peptidoglycan layer

O

What’s going on here?

membrane

Peptidoglycan layer

O

The beta lactam ring is broken! This is a beta-lactamase.

membrane

Peptidoglycan layer

O

membrane

Peptidoglycan layer

O

membrane

Peptidoglycan layer

And since the lactamase has been used, more is produced.

membrane

Peptidoglycan layer

And since the lactamase has been used, more is produced.

membrane

Peptidoglycan layer

And since the lactamase has been used, more is produced.

So this little staph aureus is resistant to beta lactam drugs like penicillin and amoxicillin!

But what about the others?

aah

aah-CHOO!

A virus that infects bacteria, a bacteriophage!

A virus that infects bacteria, a bacteriophage!

And it’s injecting its genome.

A virus that infects bacteria, a bacteriophage!

And it’s injecting its genome.

Along with the beta-lactamase gene from the resistant staph aureus!

Now he’s resistant too!

And pretty soon the bacteriophage spread the resistance to almost all of the staph aureus all over the developed world!

Resistant staph aureus can be around with penicillum without worry.

Resistant staph aureus can be around with penicillum without worry.

He lives wherever he pleases! The penicillin does nothing anymore.

Until one day…

Until one day…

What happened?

membrane O COOH

membrane O COOH

membrane O COOH

membrane

OCOOH

membrane

O

COOH

It’s clavulanate, a beta lactamase inhibitor!

membrane

O

COOH

It’s clavulanate, a beta lactamase inhibitor!

It destroys the beta lactamase with its suicide beta lactam ring. It does not trigger increased production of beta lactamase!

membrane

O

COOH

It destroys the beta lactamase with its suicide beta lactam ring. It does not trigger increased production of beta lactamase!

COOH

And now a penicillin analogue like amoxicillin can come in and do its job.

It’s clavulanate, a beta lactamase inhibitor!

membrane

O

COOH

It destroys the beta lactamase with its suicide beta lactam ring. It does not trigger increased production of beta lactamase!

COOH

And now a penicillin analogue like amoxicillin can come in and do its job.

It’s clavulanate, a beta lactamase inhibitor!

O

COOH

It destroys the beta lactamase with its suicide beta lactam ring. It does not trigger increased production of beta lactamase!

COOH

And now a penicillin analogue like amoxicillin can come in and do its job.

It’s clavulanate, a beta lactamase inhibitor!

But as long as there are no beta-lactamase inhibitors, they’ll still be resistant to beta-lactam antibiotics, right?

Wrong.

But as long as there are no beta-lactamase inhibitors, they’ll still be resistant to beta-lactam antibiotics, right?

membrane

O COOH

What’s this? It looks like penicillin except with a funny new side chain.

membrane

O COOH

What’s this? It looks like penicillin except with a funny new side chain.

It’s a synthetic penicillin, methicillin (we learned about its cousin nafcillin in class).

membrane

O COOH

What’s this? It looks like penicillin except with a funny new side chain.

It’s a synthetic penicillin, methicillin (we learned about its cousin nafcillin in class).

membrane

O COOH

What’s this? It looks like penicillin except with a funny new side chain.

It’s a synthetic penicillin, methicillin (we learned about its cousin nafcillin in class).

membrane

O COOH

What’s this? It looks like penicillin except with a funny new side chain.

And now the beta lactamase can’t reach the beta lactam ring to do its job.

It’s a synthetic penicillin, methicillin (we learned about its cousin nafcillin in class).

membrane

O COOH

What’s this? It looks like penicillin except with a funny new side chain.

It’s a synthetic penicillin, methicillin (we learned about its cousin nafcillin in class).

And now the beta lactamase can’t reach the beta lactam ring to do its job.

O COOH

What’s this? It looks like penicillin except with a funny new side chain.

It’s a synthetic penicillin, methicillin (we learned about its cousin nafcillin in class).

And now the beta lactamase can’t reach the beta lactam ring to do its job.

This staph aureus was taken out by a different drug entirely!

membrane

O COOH

Look! A celphalosporin! It’s a new drug with the structure of a penicillin except...

membrane

O COOH

Look! A celphalosporin! It’s a new drug with the structure of a penicillin except...

It has one more carbon. Look, a six-carbon ring!

membrane

O COOH

Look! A celphalosporin! It’s a new drug with the structure of a penicillin except...

Along with its hydrogen atoms.

It has one more carbon. Look, a six-carbon ring!

HH

membrane

O COOH

Look! A celphalosporin! It’s a new drug with the structure of a penicillin except...

It has one more carbon. Look, a six-carbon ring!

HH

Along with its hydrogen atoms.

membrane

O COOH

Look! A celphalosporin! It’s a new drug with the structure of a penicillin except...

It has one more carbon. Look, a six-carbon ring!

HH

Along with its hydrogen atoms.

membrane

O COOH

Look! A celphalosporin! It’s a new drug with the structure of a penicillin except...

It has one more carbon. Look, a six-carbon ring!

The beta lactamase no longer fits. The cephalosporin will chop up the wall just like penicillin!

HH

Along with its hydrogen atoms.

membrane

O COOH

Look! A celphalosporin! It’s a new drug with the structure of a penicillin except...

It has one more carbon. Look, a six-carbon ring!

The beta lactamase no longer fits. The cephalosporin will chop up the wall just like penicillin!

HH

Along with its hydrogen atoms.

membrane

O COOH

Look! A celphalosporin! It’s a new drug with the structure of a penicillin except...

It has one more carbon. Look, a six-carbon ring!

The beta lactamase no longer fits. The cephalosporin will chop up the wall just like penicillin!

Along with its hydrogen atoms.

membrane

O COOH

Look! A celphalosporin! It’s a new drug with the structure of a penicillin except...

It has one more carbon. Look, a six-carbon ring!

The beta lactamase no longer fits. The cephalosporin will chop up the wall just like penicillin!

Along with its hydrogen atoms.

O COOH

The beta lactamase no longer fits. The cephalosporin will chop up the wall just like penicillin!

Look! A celphalosporin! It’s a new drug with the structure of a penicillin except...

It has one more carbon. Look, a six-carbon ring!

Along with its hydrogen atoms.

Over time some staph aureus bacteria have developed new things like the beta lactamases

that will chop up synthetic penicillins like methicillin or nafcillin

O COOH

Over time some staph aureus bacteria have developed new things like the beta lactamases

that will chop up synthetic penicillins like methicillin or nafcillin

or the cephalosporins.

O COOH

O COOH

So researchers will add more modifications to make the bacterial weaponry no longer work.

O COOH

O COOH

And bacteria will again come up with ways to chop up these drugs. And so on.

O COOH

O COOH

After a long enough time, one particular staph aureus underwent a very strange mutation.

After a long enough time, one particular staph aureus underwent a very strange mutation.

After a long enough time, one particular staph aureus underwent a very strange mutation.

Let’s take a closer look…

After a long enough time, one particular staph aureus underwent a very strange mutation.

membrane

It looks like the transpeptidase, also known as the penicillin binding protein, has changed!

membrane

It looks like the transpeptidase, also known as the penicillin binding protein, has changed!

OO COOH

Now cephalosporins and synthetic penicillins like methicillin have nothing to attack.

membrane

It looks like the transpeptidase, also known as the penicillin binding protein, has changed!

OO COOH

Now cephalosporins and synthetic penicillins like methicillin have nothing to attack.

And because of that, it’s a methicillin resistant staph aureus or MRSA.

If we were to look at his DNA, we’d find that he has something called the MecA gene.

DNA

MecA

It means that all of his offspring will also have this gene.

If we were to look at his DNA, we’d find that he has something called the MecA gene.

It means that all of his offspring will also have this gene.

If we were to look at his DNA, we’d find that he has something called the MecA gene.

It means that all of his offspring will also have this gene.

If we were to look at his DNA, we’d find that he has something called the MecA gene.

It means that all of his offspring will also have this gene.

But the MecA gene slows him down! He’ll be outgrown every time by plain-old methicillin susceptible staph aureus (MSSA).

But the MecA gene slows him down! He’ll be outgrown every time by plain-old methicillin susceptible staph aureus (MSSA).

But the MecA gene slows him down! He’ll be outgrown every time by plain-old methicillin susceptible staph aureus (MSSA).

OO COOH

OO COOH

Unless there are antibiotics like methicillin or cephalosporins around.

Just for that reason, MRSA loves to live in hospitals!

So if people are in the hospital for long enough, they’ll often get colonized by MRSA. For that, he is known as hospital-acquired MRSA (HA-MRSA).

But as soon after they get home, they get recolonized by MSSA.

And up until recently HA-MRSA stayed in and around hospitals.

And up until recently HA-MRSA stayed in and around hospitals.

Until one day…

And up until recently HA-MRSA stayed in and around hospitals.

Until one day…

DNA

MecA

One particular MRSA developed a smaller and more efficient MecA gene.

And can now compete with MSSA out in the community.

And can now compete with MSSA out in the community.

And can now compete with MSSA out in the community.

OO COOH

OO COOH

But is still resistant to the beta lactam drugs!

Now a good amount of the population in the community is colonized with this new, competitive MRSA, known as community-acquired MRSA (CA-MRSA).

Now a good amount of the population in the community is colonized with this new, competitive MRSA, known as community-acquired MRSA (CA-MRSA).

There are a few classes of other antibiotics out there which work on other bacterial targets to beat HA-MRSA and CA-MRSA. Resistance against these drugs is slowly but surely emerging.

One thing’s for sure, Staph aureus and Catalase will be around for a long, long time.

The end.

One thing’s for sure, Staph aureus and Catalase will be around for a long, long time.