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While some might wax nostalgic about the olden days,
they weren’t necessarily golden if you cut yourself on a tree branch,
had a tooth abscess, or caught gonorrhea.
At least until Alexander Fleming accidentally discovered penicillin from
some mold juice that found its way into a petri dish of bacteria in 1928.
Or, more accurately, until scientists at Oxford University figured out
how to isolate and purify penicillin to turn it into a drug in the 1940s.
Suddenly, many infections went from life-threatening to an inconvenience,
and the age of antibiotics took off.
But now they’re so common that doctors are running into a problem:
the targets of these drugs are refusing to be killed, developing resistance to
our treatment arsenal and threatening a return to the medical days of yore.
If we’re to solve this problem, we might have to step back and pay due deference
to the true inventors of antibiotics: the very bacteria we’re trying to fight.
Because bacteria and antibiotics have coexisted for a long time before
our ancestors hit on the idea of walking upright.
And to learn to use them properly,
we might have to learn from those masters.
What makes antibiotics useful in medicine is that they target bacteria
but leave human cells untouched; ideally, anyway.
Most either kill bacteria outright, or prevent them from reproducing so that
the population eventually dies off.
But they accomplish this in different ways.
Penicillin, the prototype antibiotic works by interfering with the
production of a molecule that makes bacterial cell walls strong.
Animal cells don’t have cell walls, and no use for that molecule,
so they aren’t affected at all.
But its absence leaves bacterial cells so fragile that they burst and die.
Another class of antibiotics, sulfa drugs,
work by interfering with the production of folic acid.
Animal cells do need folic acid, but we get it from our diets.
But since folic acid can’t penetrate bacterial cells, they need to make it themselves.
And if they can’t make it, they can’t grow and reproduce, while the host’s cells
are
happily chugging along, full of folic acid from last night’s dinner.
There are more than 100 antibiotics currently in clinical and agricultural use,
and although the OG, penicillin, came from mold,
most of those actually come from soil bacteria.
And it’s not, like, an accident that they do that.
Antibiotics have an ecological function for the bacteria that make them.
Though what that is exactly, we’re still studying.
A bacterium produces antibiotic molecules that diffuse out through the soil,
creating a halo around itself.
Close to the cell, the concentration is highest,
and it drops off as you move further away.
So we’ve traditionally thought that antibiotics are a weapon bacteria use to kill
other competing microbes in an area so the producer bacteria can reign supreme.
But obviously we don’t just make sick people eat dirt and hope for the best.
Instead, we isolate and purify the specific
antibacterial compound those soil bacteria are producing.
Then, we figure out a dose that will be strong enough to take out the infection
even as our livers try to process it out of our bodies.
Which is… a lot.
So when we take antibiotics as drugs, they’re often a much higher concentration
that lasts much longer and works at a much larger scale than they do in nature.
This development and dosing process is in a constant race against the bacteria
we’re fighting off developing resistance to the drugs we’re trying to kill them with.
And that resistance is genetic.
The target bacteria either develop genetic mutations that allow them to survive
the antibiotic attack, or receive those genes
from other bacteria that are already resistant.
Those genes can work in a handful of different ways.
In general, they keep the antibiotic molecule from interacting
with whatever that molecule targets to murder bacteria.
When bacteria become resistant, we start needing higher and higher doses
of antibiotic to reach an effective dose,
and some antibiotics just stop working altogether.
In fact, we’re at a point where most new antibiotics have fewer than 10 years of
widespread use before resistance is too high for the drug to be helpful.
New ones can either be discovered in the wild or developed in a lab,
but overall, we’re starting to run low on options.
But as much as we may think about antibiotic resistance
as a side effect of the antibiotic age, it’s really not.
Bacteria have had antibiotic genes for a long,
long time before people started using them for drugs.
They’ve been around for at least 40 million years,
and possibly up to two billion years.
And we think they’ve had antibiotic resistance genes for just as long.
So you might expect that it plays out in the wild the same way it does in the clinic,
where antibiotic resistance makes specific antibiotics
totally useless after a while, and new ones would have to evolve.
But that’s not how it plays out in the wild.
In nature, antibiotics and the bacteria that are
resistant to them co-exist more than they compete.
In fact, the genes that code for an antibiotic molecule often exist in the same
stretch of DNA as the genes that code for resistance
to that exact same antibiotic molecule.
Which may seem counterintuitive.
But bacteria need to make sure they don’t kill themselves with their own antibiotics,
so having the genes so close together probably
helps with using both at the same time.
It also means bacteria can easily share both genes at the same time.
See, bacterial ecosystems are way more than just
a biological version of the game Space Invaders.
They’re are tons of bacteria from multiple species
engaging in complex interactions that we can’t even see.
And since at least 1990, scientists have been thinking that maybe antibiotics
didn’t actually evolve to be weapons at all, or at least not primarily weapons.
And that idea has really been gaining traction in the 21st century.
Maybe they, and the resistance they co-evolved with,
are actually tools of community building.
You wouldn’t think that secreting a toxic molecule
would help you play nice with other microbes.
But there are a bunch of ways that actually can be the case.
So let’s get into a few.
There’s a lot of evidence that at low levels,
microbes actually use antibiotic compounds as signalling molecules.
In other words, they talk with antibiotics.
The message they send can influence the way microbes copy genetic instructions
and build proteins, especially proteins that help them
adapt to their environment, get energy, and protect themselves.
Sometimes microbes can make all of the tools to protect themselves
against attackers, but aren’t able to push the button to
start up those genes to make those tools.
So signalling molecules from other species tell these microbes
when it’s time to turn on those genes, basically flipping the switch for them.
Which means in this case, antibiotics could function
as either a warning shot or a goodwill gesture.
Depending on whether they switch on helpful or harmful genes.
It’s a way of telling your neighbors to back off, or asking to work together.
Antibiotic resistance can also help different species work together
to protect their whole community against antibiotics seeking to kill them.
Some species stick to each other and create a super-tough sheet called a
biofilm that can help protect them from antibiotics
by basically acting as an antibiotic-proof raincoat.
Some species can’t form their own biofilm, so they’ll wiggle their way into
someone else’s to take advantage of the protection that that tough sheet offers.
Kind of like when your dog wedges itself between
you and your partner on the couch during a thunderstorm.
And in other cases, antibiotic resistant molecules work in a similar way
to antibiotics, with that concentration gradient spreading out generating a force field
around the producer microbe that inactivates all the antibiotics nearest to it.
Other species that aren’t resistant to the antibiotic in question can
slip inside their neighbor’s force field for protection, so they survive even though
they don’t have the ability to inactivate the antibiotic themselves.
By working with neighboring microbes,
every microbe doesn’t have to be resistant to every antibiotic.
Members can work together so the community can protect itself,
even if the individuals can’t.
But all of those strategies focus either on antibiotics or antibiotic resistance.
They don’t explain why both might occur together in the same organism.
In 2021, researchers in New York described it like a secret society.
If you’re going to be living in a community that relies on cooperation
when resources are limited, you’re going to want to maximize the chances that
the new guy is bringing something to the table,
making him worth splitting your resources with.
In this view, the halo of antibiotic secreted by a particular community
represents a gauntlet that makes it difficult for outsiders to get close.
But if a new microbe can survive the microbial hazing and get close enough,
it gets initiated into the club by the members transferring the genes that code for
both the antibiotic it just made its way through,
and whatever molecules grant resistance to that antibiotic.
Remember, we often find these on the same short pieces of DNA,
so it’s a package deal.
Then the new microbe is able to contribute its genes to rest of the club,
like maybe bringing resistance to an entirely
different antibiotic or protection against some other toxin.
And if they get separated, knowing the secret handshake of antibacterial resistance
means the new guy can just walk right up,
and the bacteria that are already there will know he’s cool.
Then the new guy can also secrete the antibiotic,
which our colony is fine with, because they’re resistant.
But other nearby bacteria may not be, so with each new member recruited,
the colony is able to exert their communal antibiotic sphere
a little farther and clear out competing organisms.
That gives the colony more room and resources, plus the ability to expand their
new friend filter even further, bringing even more beneficial genes into the fold.
In this case, without antibiotic resistance,
the antibiotics would actually be useless.
They both need to occur together.
And they both facilitate community cooperation.
Pull all of this together, and you end up with an ecosystem with multiple roles.
You have a bacterial colony that produces an antibiotic
in high concentrations close in, and lower concentrations further out.
Close in, that antibiotic kills all of the microbes that are sensitive to it, opening
up
space for bacteria that are resistant to move in and interact with the original colony.
Meanwhile, the bacteria a little bit further out,
those still coming in contact with the antibiotic but not in the kill zone,
are having their genes turned on or off by the antibiotic in question,
changing how they function.
The sub-lethal dose of antibiotics can also select for them to
evolve their own resistance genes, letting them gradually get closer.
So despite antibiotic and resistance genes existing for millions of years in nature,
they haven’t run into the situation that we are in currently in
the pharmaceutical space, where resistance is
starting to make antibiotics basically useless.
And that may be because we’re just using them, well, wrong.
Historically, we’ve focused on antibiotics as molecules secreted by individual cells,
and resistance as a completely separate thing that
develops in response to that antibiotic.
But that just doesn’t seem to be how it works in the wild.
It’s actually seeming more and more likely that antibiotic-producing bacteria
evolved to exist in communities, and are intrinsically
intertwined with antibiotic-resistant bacteria.
Now, that’s not to say that we should avoid
the antibiotics currently being prescribed.
Right now, they’re the best weapon we have against so many diseases.
But as we develop the next generation of antibiotics, rethinking these processes as
two sides of the same coin could change the way we approach antibiotic drugs.
It may also be worth looking at how different species of microbes
interact and how whole communities might provide protection.
In nature, combinations of antibiotics end up having
different effects than when an antibiotic compound is isolated.
So while many people are warning that antibiotic resistance
is leading to the end of the age of antibiotics, maybe it doesn’t have to.
Maybe we just need a new way of looking at the problem that focuses on how we
can use resistance to our advantage and leverage its relationship with antibiotics.
In other words, in the crusade against antibiotic resistance,
maybe it’s time to try making love, not war.
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