This is Staphylococcus aureus.

And this  is VRSA.

Just like in the card game War,   the two of bacteria Staphylococcus aureus  is going to lose to the five of antibiotics   penicillin but the Ace of bacteria VRSA is  going to beat out our five of penicillin.

Now how has this seemingly harmless game  of war turned into a real life game of   war against antibiotic resistant super bugs,  truly the most horrifying thing in science to   me?

Well cause we don't have an ace of  antibiotics to win this ever evolving.

Does this guy not get that hydrogen?

It doesn't  show it in my diagram but it feels like this   guy should get that hydrogen.

Oh it ends up  over here.

Okay okay all right.

We're good.

Bacteria are simple.

They grow.

They have  abilities..

The make more bacteria.

They   die.

They don’t have wants.

They don’t have  motivations.

But they are $%@!ing good at   growing and making more of themselves.

And when they do, they can make us sick.

Saphylococcus aureus is a pretty simple, common  bacteria found on the skin and respiratory tract.

About 30% of us have it in our noses.

But if it  winds up in the wrong place, like an open wound   or inside your body, it can cause dangerous,  life-threatening infections.

It’s basically   the 3 of Hearts.

Most of the time it’s fine, but  in the right circumstances, it can take you down.

Because antibiotic resistance, not just in S.  aureus but in lots of different kinds of bacteria,   is scary.

It’s already killing over a million  people each year, and it’s associated with about   5 million deaths.

Even when it’s not killing  people, antibiotic resistance leads to longer   hospital stays, and puts procedures like cancer  treatment, bone transplants, and c-sections at   increased risk.

The list of diseases that are  getting harder to treat because of growing   antibiotic resistance include “pneumonia,  tuberculosis, blood poisoning, gonorrhea,   and foodborne diseases.” And yes I did say  there’s even a new strain of antibiotic resistant   gonorrhea that has led to this simultaneously  terrifying and hilarious graphic from the CDC.

In 1929, Alexander Fleming was a gross,  messy scientist and discovered penicillin.

You probably know the story: he left out  a plate of bacteria, came back to the lab   to find some mold growing on it, ew, and then  realized that the mold seemed to be inhibiting   the growth of bacteria in the spots around it.

Bam.

Our first safe and effective antibiotic.

Because replicating bacteria can pose a real  health threat, antibiotics need to do one of   two things: either kill the bacteria outright  or inhibit its growth.

And while there are more   than 100 available out there now, you can group  them into categories based on their molecular   structure and how they work: by disrupting the  cell wall, inhibiting DNA synthesis, inhibiting   RNA synthesis, by disrupting protein production,  or by interrupting the synthesis of an important   vitamin, folate.

Break any of these key systems  and the bacteria’s not gonna reproduce well.

Penicillin attacks the cell wall.

It contains  a thiazolidine ring, an acidic side chain,   and a beta-lactam ring.

That beta-lactam ring is  the key for the bacteria to defeat the antibiotic.

Bacterial cells contain proteins involved  in forming the cell walls that penicillin   can bind to.

Scientists very creatively named  these proteins “Penicillin binding proteins.”   When penicillin binds, the cell wall proteins  have a harder time binding to each other,   so the cell wall of bacteria like S. aureus  weak and leaky.

If the cell wall is unstable,   the bacteria can’t do the only thing it  does: grow or make more of itself.

But   if you break that Beta-lactam ring,  the antibiotic won’t work anymore.

When bacteria, including S. aureus replicate,  sometimes a tiny change in the DNA happens,   making it a little bit different.

And in 1942, a  few years before penicillin was even commercially   available, scientists found new strains of S.  aureus that contained mutations which allow them   to produce enzymes called beta-lactamases that  break down the beta-lactam ring of penicillin.

The beta-lactam ring fits right into a pocket in   many of these enzyme structures.

One of  the amino acids in this pocket, a serine,   attacks the carbonyl carbon of the peptide  bond, breaking it.

For a moment, there’s   an intermediate molecule where the now-open  beta-lactam ring is connected to the enzyme,   but a water molecule comes in to complete the  hydrolysis reaction, leaving behind an unchanged   enzyme hat can go on and be free to move on  and destroy another molecule of penicillin.

So no matter how much penicillin you threw at it,  the new S. aureus could survive.

By the 1960s,   more than 80% of isolated strains of  Staphylococcus were penicillin resistant.

Unfortunately, the response to what we now know  is a horrifying development where bacteria can   and will defeat medication, was kind of muted.

Though Great Britain took some strides to try   and fight back with the Swann report in 1969,  which banned using clinically useful antibiotics   in agriculture to try and keep bacteria from  becoming resistant to them.

Here in the US,   doctors continued to prescribe lots and lots  of antibiotics, and basically no action was   taken to try and prevent resistance from  growing in agricultural settings.

Great.

Antibiotic resistance is when a microorganism like  bacteria is no longer responding to antibiotics   they were previously susceptible to, and  that were previously active in treating   infections.

This makes infections harder to  treat and increases the risk of them spreading.

There are four ways, really, that  bacteria can become resistant to a   drug.

It can inactivate the drug, like S.  aureus started doing to penicillin.

It can   reduce the amount of drug that is pulled  into the cell, or it can do a better,   faster job of kicking the drug out of the  cell, a process known as drug efflux so   that the antibiotic doesn’t have a chance  to reach its target.

Or, it can change   the shape or structure of targets inside the  bacterial cell that the antibiotic binds to.

In the late 1950s, doctors and scientists  tried to fight S. aureus with methicillin.

Methicillin is a semi-synthetic derivative of  penicillin.

It was developed to be resistant to   the beta-lactamases that broke down  penicillin, with a large side group   that would inhibit binding to the  enzymes.

No binding, no breakdown.

But, methicillin can still bind to  the bacteria’s penicillin-binding   proteins to keep them from doing  the only thing that bacteria does:   grow and divide.

And it worked for a  moment.

But bacteria quickly rendered   methicillin ineffective too, and spread that  resistance through horizontal gene transfer.

Horizontal gene transfer means that the  bacteria aren’t just transferring DNA   “down” to the next generation of bacteria.

They can also transfer it “horizontally” to   other bacteria they bump into.

This would  be like me bumping into Jennifer Doudna or   Carolyn Bertozzi and getting a download of  their Nobel-prize winning DNA.

I would love   that.

And horizontal gene transfer is  exactly what happened with methicillin.

Genes mecA and mecC were transferred to S.  aureus.

MecA and MecC work by not breaking   down methicillin but by creating alternative  penicillin binding proteins that don't allow   methicillin to bind them as well their change  shape.

That means that the drug has no effect   and the bacteria can keep building cell walls and  growing even in the presence of the antibiotic.

Now, we’re left with Methicillin Resistant  S. aureus: MRSA.

MRSA can cause incredibly   painful skin lesions that  can “burrow” into the body   all the way down to the bones and joints  and when it winds up in surgical wounds,   it’s not comfortable.

It’s in fact  incredibly dangerous and life-threatening.

Vancomycin became the next line of defense  against MRSA.

Vancomycin looks very different   from penicillin and methicillin because it  is very different.

It’s a big glycopeptide,   meaning it has a peptide backbone, much like  a protein, with sugar molecules connected to   the side chains.

Like many antibiotics, it was  discovered, not invented.

Scientists isolated   it from a species of fungus called Amycolatopsis  orientalis in 1955.

This fungus came from a soil   sample taken from a jungle in Borneo.

And  this is how we find a lot of antibiotics:   we take a sample of soil from somewhere and  put dilute samples of that onto a plate covered   in bacteria.

If the bacteria stops growing in  the spot where you’ve added your sample, it’s   likely something in that sample has antibiotic  properties.

And as you can imagine, figuring out   exactly what part of that sample is important is  hard, and then figuring out its structure, is even   harder.

Vancomycin’s structure, which, clearly,  is very complex, wasn’t figured out until 1981.

Vancomycin works by stopping cell wall  proteins from cross linking together   in a growing bacteria.

This destabilizes the  walls so the guts of the bacteria leak out,   and it dies.

And this worked  to stop MRSA… for a while.

Once again, MRSA got a hand from a friend.

In the 80s, gut bacteria called enterrococci   started to show resistance against  vancomycin.

Again, the genes involved   create resistance by changing the shape of  the proteins that the antibiotic binds to.

And now, in recent years, these genes have  once again been handed over to S. aureus,   creating vancomycin resistant S. aureus,  or VRSA.

It’s a slam dunk for the bacteria:   different strains are still susceptible to some  levels of the antibiotic.

But it’s not good.

Antibiotic use can for sure accelerate  the rise of resistance, but resistance   itself is a natural process.

Because there  are really three categories of resistance:   natural intrinsic resistance meaning the bacteria  was resistant before it ever met the antibiotic,   natural induced resistance, meaning genes  in the bacteria are activated by exposure   to clinical levels of antibiotic,  or acquired resistance, meaning the   appearance of DNA mutation that occurred during  replication or DNA transfer in that bacteria.

And another the thing is that antibiotic  resistance doesn’t only develop in “bad”   bacteria.

There is bacteria everywhere.

On your skin.

In your gut.

On your dog,   in the soil, on your food… and a lot  of it is very good, helpful bacteria,   or honestly just neutral bacteria doing its  own thing and not bothering us.

But when any   of that bacteria encounters antibiotics from our  medicines or agricultural use or antibacterial   hand soap… it can develop resistance.

And then it  can transfer that resistance to the bad bacteria.

And pretty much all of the antibiotics  we’ve talked about so far have been   “found” not invented.

Penicillin was on  a dirty lab plate.

Vancomycin came from   a jungle soil sample.

And while  we’re looking, and looking hard,   one of the last antibiotics that got approved  was found on a mountain in Turkey in the 1980s.

The 80s!

Before the Berlin Wall came down!

So  finding these in nature is a slow, slow process.

So how do we get an antibiotic Ace card?

Well for MRSA and VRSA specifically, doctors are  taking lots of combinatorial approaches, using   pairings of different antibiotics to try and knock  it down.

But we need whole new strategies here.

And somebody’s gonna complain  if I don’t mention AI so yes,   one of the new strategies is AI.

There’s lots  of buzz around AI, including because it can   allow researchers to screen whole libraries  of candidate antibiotic molecules digitally,   instead of having to put them to the test  on bacteria in the lab.

This can help you   narrow down potential successful candidates  quickly.

Another place this can be useful   is for predicting how modifications on current  antibiotics might make them more effective.

This   is helpful in hypothesis generation but AI is not  yet like “the solution” to antibiotic resistance.

Bacteriophages, on the other hand… they’re  viruses that naturally infect bacteria,   the ones that look a lot like  space invading spiders.

So there   are lots of groups trying to use them  to fight antibiotic resistant bacteria.

This is actually a pretty old process: in  1917, scientists found phages in the stool   of sick patients right before they recovered  from bacterial infections, and realized that   maybe they could use this as a treatment.

And  work on this started until antibiotics came   along and we all got lost in an antibiotic  heyday and thought “hey these are awesome,   let's use them all over the place and create  a world full of bacteria we can’t kill!” So bacteriophages are making a comeback.

For one  thing, they are really specific: they only infect   and kill one specific bacteria, unlike antibiotics  which often kill many different kinds of bacteria.

This reduces the chance for spread of resistance.

Bacteriophages also usually need just a few doses   to be effective, and are pretty well tolerated  because they don’t affect our own human cells.

But, you need to find the right bacteriophage to  kill the exact right bacteria, which is a tough,   tough process.

It can and is done in  special cases, specifically for patients   with infections resistant to lots of different  antibiotics.

But this has to be contracted out   to speciality companies, so it’s not as easy  as filling a prescription at the drug store.

Rather than finding these bacteriophage,  there’s a lot of interest now in creating   new CRISPR-bacteriophage combos.

CRISPR is the  hot new genetics tool that let’s you slice and   dice specific pieces of DNA.

So if you create  a CRISPR construct that specifically targets,   say, MRSA DNA, and pop it into a  bacteriophage that can infect Staph,   you might be able to specifically kill a  MRSA strain while leaving all the other   bacteria in your body alone.

A little  like a trojan horse full of DNA scissors.

So tools are coming.

They are.

But not  soon enough.

In 2019 the World Health   Organization called antimicrobial resistance  one of the top ten threats to global health.

They estimate that it could kill as many  as 10 million people per year by 2050.

That’s it.

That’s the end.

I’m just  terrified.

Like I actually am though