So, when we take antibiotics because of a bacterial infection, billions of bacteria are suddenly attacked by antibiotics.

They struggle to repair damage, maintain their structures and continue essential functions just to stay alive.

This ultimately weakens or kills the cells.

And as you can imagine, this is pure stress for the bacteria.

One that we take advantage of.

This article series takes you on a journey through the microscopic war between bacteria and antibiotics. Across five articles, we will explore how antibiotics attack bacteria, how bacteria overcome them, become resistant and how evolution pushes bacteria to survive the antibiotic war.

In this first part of the series, we explore how different classes of antibiotics work, while focusing on the most commonly used antibiotics. Once you understand these mechanisms, you will better understand how and why bacteria fight back, evolve and develop resistance.

Antibiotics attacking bacterial cells by stopping cell division

Bacteria have a rigid cell wall made of peptidoglycan to maintain their shape and internal pressure and to protect them from the environment. Without the ability to build or repair the cell wall, bacteria become fragile and burst easily.

This vulnerability is precisely what antibiotics from the β-lactam family exploit. You have probably heard of penicillin, one of the most well-known members of this class. Other similar antibiotics are amoxicillin and cephalosporins.

How these antibiotics work is pretty simple but devastating to bacterial cells: they block the so-called penicillin-binding proteins. These enzymes sit in the cell wall where they are responsible for building and cross-linking it.

So, when a bacterium gets hit by a β-lactam antibiotic, it loses the ability to divide. Basically, every time it tries to divide, it will burst like a water balloon.

Antibiotics sabotaging bacteria’s genetic machinery

Every bacterial cell carries instructions for life in its DNA, the molecule that stores genetic information. Before dividing, bacteria copy their DNA and then share it with their daughter cells.

Bacteria also make RNA, the molecule that executes the instructions stored in DNA. RNA comes in different types with distinct roles, but it is fundamentally needed to make proteins from DNA.

Some antibiotics exploit this vulnerability by inhibiting one of the cell’s information-processing machineries. This fundamentally interferes with DNA or RNA synthesis. If a bacterium can’t produce DNA or RNA, it can’t divide or maintain its genetic integrity, leading to cell death.

The antibiotic class fluoroquinolones inhibits DNA production. For example, ciprofloxacin freezes the enzymes that help bacteria copy their DNA. When DNA replication stalls, bacteria cannot divide. They accumulate damage and eventually die.

In comparison, rifamycins inhibit RNA synthesis. These antibiotics bind to the RNA polymerase, the enzyme that produces RNA from DNA. They thereby block the first step in protein production.

It’s like cutting electricity to an entire factory; without RNA, the cell cannot produce proteins, halting metabolism and growth. This is highly stressful to bacteria and can quickly kill them.

Antibiotics blocking protein production: The ribosome hijackers

Other antibiotics directly inhibit the protein production step: To build proteins, bacteria produce a temporary working copy of those DNA instructions, the so-called messenger RNA or mRNA.

This molecule travels to the ribosome, which reads the mRNA and makes proteins from it. Since proteins are essential for metabolism, movement, growth and cell division, no cell can function without them.

Some antibiotics, like tetracycline, take advantage of this protein production vulnerability. By interfering with ribosomes, these antibiotics prevent them from producing proteins and eventually the bacterial cells from functioning.

Interestingly, not all protein-production inhibitors kill bacteria in the same way. Some antibiotics are bacteriostatic, which means they freeze growth without immediately killing the cell. The bacteria cannot make new proteins, so they can’t divide or repair themselves. Instead, the existing proteins remain active for a while, allowing the cell to survive in a weakened state.

Others, like aminoglycosides, are bactericidal. Instead of simply blocking ribosomes, they cause the ribosome to make mistakes and produce misfolded proteins. These faulty proteins build up inside the cell and damage essential structures, overwhelming the bacterium, so it eventually dies.

Antibiotics disrupting metabolic pathways

Lastly, some antibiotics target essential metabolic pathways that bacteria need to survive. For example, folate is an essential vitamin that all organisms need to grow and reproduce, and most bacteria have proteins to make their own folate. So, when antibiotics block these folate-producing proteins, the bacterium will eventually run out of folate and lose the ability to grow.

How different antibiotics kill bacteria

As we’ve seen in this post, antibiotics can impact bacteria in many different ways. But they all have the same goal: do the biggest damage possible. Antibiotics can damage a bacterium’s DNA, its protein production machinery, metabolic pathways or the cell envelope.

This damage is essentially stress for the bacterium: they must repair the damage or adapt their metabolisms to it. If they cannot cope with the damage or the stress, they’ll die. And remember, this was basically the antibiotic’s goal from the beginning.

But be aware: this stress can be both lethal and a driving force for bacterial evolution. As they learn to cope with the antibiotic and the stress, they become resistant. And in future articles, we will explore these bacterial learning processes and how they help make bacteria resistant to antibiotics.

The post How Antibiotics Kill: The Weapons We Use Against Bacteria appeared first on Bacterialworld.
Bacterialworld - A blog about bacteria: from scientific studies to vivid stories about the fascinating bacterial world

But what do bacteria and fungi use antibiotics for? Why do they produce them? And what are the advantages of microbes having antibiotics as molecular weapons?

What are antibiotics?

The father of antibiotics, Selman Waksman, first used the word antibiotics for any small molecule made by a microbe that can inhibit the growth of other microbes.

So, microbes – especially bacteria and fungi – use antibiotics to kill other microbes. These other microbes can be bacteria, fungi or bigger organisms. Not viruses though!!!

Why not viruses?

Because antibiotics bind and inhibit cellular machines in living organisms. These molecules often bind to so-called targets. Antibiotic targets can be proteins or enzymes that make for example the cell wall, other proteins or components of the respiration complex.

These proteins are generally essential. So, when antibiotics inhibit the proteins, the cells are missing these essential functions. And without them, they cannot survive and die.

Hence, like other bacterial toxins, antibiotics are lethal.

Interestingly though, bacteria and fungi make antibiotics from simple building blocks. These are present in every cell and can be amino acids, lipids or even sugars.

But instead of using these building blocks for their normal functions, microbes link them together in different ways. With this, they create new – and fancier – molecules that barely resemble the original blocks.

Then, they transport these antibiotics to the outside or send them off in outer membrane vesicles. When the antibiotic hits another microbe, there are two possibilities: either the microbe is resistant to the activity of the antibiotic or it dies from it.

But what about the microbe that produces the antibiotic? Is it resistant to the antibiotic itself?

Why are microbes that produce antibiotics not get killed?

Since antibiotics are meant to KILL other microbes, then why do producing microbes not get killed by their own antibiotics? The answer is self-protection!

Whenever bacteria or fungi produce antibiotics, they always also produce some sort of self-protective means. Just as when bacteria produce other toxins, they always need to make sure they are not killed by their own weapons.

These self-protectors usually keep the antibiotic in an inactive state. For example, they completely surround the antibiotic molecule so that it cannot bind to its usual target within the cell. Another strategy is to add a small molecule to the antibiotic – again to keep it from binding to its target.

Then, when the microbe is ready to transport the antibiotic outside of the cell, it takes the self-protection off the antibiotic. This releases only the toxic part – the antibiotic itself – into the surrounding.

Note, however, that these self-protection mechanisms are not antibiotic resistance mechanisms. Self-protection mechanisms are meant to inactive antibiotics only temporarily. Hence, these mechanisms are reversible. The antibiotic can still become active and thus toxic.

Resistance mechanisms, on the other hand, are meant to inactive antibiotics permanently. Hence, these mechanisms are irreversible. Since this usually completely destroys the antibiotic, it cannot become active anymore.

But what triggers microbes and especially bacteria to produce antibiotics? How do antibiotics help the producing cell in their daily circumstances?

Why do bacteria produce antibiotics?

To answer this question, we need to look at where the bacteria live that make antibiotics. And two-thirds of the known antibiotics are made by bacteria from the Actinobacteria family. Within this family, Streptomyces is the best-known member that produces half of all known antibiotics.

Another example is bacteria from the Myxococcus family. So, where do Streptomyces and Myxococcus bacteria live? Interestingly, these bacteria call the soil their home.

And in the soil, they often confront lots of friends and foes. And they need to constantly fight for their own survival.

Myxococcus is known as a wolf-pack predator because it kills its prey in massive attacks. Colonies of Myxococcous roll over their prey, secrete antibiotics and thus kill them and feed on them.

Streptomyces, on the other hand, uses its antibiotics a bit more civil.

To move in the environment, Streptomyces bacteria grow as long filaments throughout the soil. They build long chains and branch out into the soil as multicellular organisms. These branches are filled with Streptomyces cells but also spores so that the bacteria can extend to new places.

When the bacteria hit a period of bad weather or don’t find much food, they release their spores as a survival strategy. Plus, they start releasing nutrients for the spores. But these nutrients also attract other organisms like bacteria.

Hence, at the same time, Streptomyces produces a huge amount of antibiotics to fend off these putative food-stealers. Like this, Streptomyces makes sure their spores are safe and can survive in their new homes for a while.

How do antibiotics produced by bacteria help others?

Like Streptomyces, lots of bacteria use antibiotics to fight off predators. This assures their own survival and that of their species.

Yet, more and more research finds that bacteria not only kill other species with antibiotics so they can survive. The killing also benefits their hosts.

For example, the bacterium Janthinobacterium lividum lives on frogs where it produces the antibiotic violacein. This antibiotic kills fungi so that the bacterium protects the frog from deadly fungal infections.

Also, a bacterium that lives in our noses is the harmless Staphylococcus lugdunensis. This bacterium produces the antibiotic lugdunin. That inhibits the harmful Staphylococcus aureus from settling down in our noses. Now, scientists look into how we could use the harmless Staphylococcus lugdunensis to protect us from infections.

Another example of microbes that produce antibiotics to help others is the three-member association of ants, Streptomyces and a fungus. Several species of ants grow fungi for food. They feed their fungi with fresh plants and let them grow in special underground gardens.

To not contaminate these fungal gardens, ants carry symbiotic Streptomyces that produce antibiotics. Like this, the antibiotics kill other microbes and keep the fungal gardens free of harmful intruders. As a thank you, the ants feed the Streptomyces and give them a place to live.

About antibiotic-producing microbes

So, just as we use antibiotics to kill harmful bacteria and fungi, antibiotic-producing microbes do the same. They want to fight off predators and assure their own survival.

When you think about it: we use their own killer weapons against them. Poor microbes!

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Bacterialworld - A blog about bacteria: from scientific studies to vivid stories about the fascinating bacterial world

Also, bacteria want to grow and flourish and reproduce. But they are only single cells so that their way of reproduction is unique. They reproduce asexually meaning you only need one parent bacterium to make two daughter bacteria.

When you think about it, bacterial cell division seems very easy: Start with one bacterium, divide it in the middle and you end up with two.

However, the mechanism of cell division is pretty complex and involves at least three tasks:

• the bacterium needs to decide WHERE to divide
• get all the needed machinery to the division site
• produce new cell envelope material to separate the two new daughter cells

How a bacterium starts cell division

As you can imagine, for most bacteria it makes the most sense to divide straight in the middle. Like this, they end up with two daughter cells of the same size.

This means a bacterium needs to find its middle and mark it. While it is not completely clear yet to researchers how bacteria find the exact middle, they know it involves a so-called Z-protein.

This Z-protein can bind two things: itself and the inside of the bacterial cell envelope. But it only binds the cell envelope where it is straight and not bent. And this is only the case in the middle of the bacterial cell envelope.

Hence, the Z-proteins bind themselves in a long chain linked to the straight cell envelope. Eventually, they form a ring on the inside of a bacterial cell. And this so-called Z-ring stays in the middle of the bacterium.

Also, the Z-ring is only stable when bacteria have enough nutrients and do not encounter any stress situations. This reassures that bacteria only divide when they have all the needed supplies.

How bacteria divide and produce two daughter cells

Once this Z-ring is stable, it recruits helper machineries to this now defined division site.

The Z-ring is a sign of an upcoming cell division. Now, the bacterium knows it needs to activate machineries to produce more cell envelope material and become longer. And to increase their cell envelopes, bacteria use ferries, tunnels and bridges to transport lipids into the cell envelope.

Like this, the bacterium becomes longer and can start the actual cell division. At the same time, the Z-ring becomes tighter and the cell envelope gets its natural bend again.

Now, two processes happen at the same time: Bacteria cut open their peptidoglycan envelope to separate the two daughter cells and also produce envelope material to close both cells.

After this happened, we have two daughter cells coming from the same parent. They both share the same cell envelope and genome. This is why we consider them identical twins.

But do all bacteria produce identical twins upon cell division?

Do bacteria always divide in the middle and produce identical daughter cells?

Yes, most bacteria are symmetrical. And when they divide right in the middle, they produce two identical daughter cells.

Researchers could even watch bacteria during this process thanks to amazing microscopy techniques. You can see the single stages of bacterial cell division and how bacteria produce the cell envelope in the image below.

Yet, the bacterium Caulobacter crescentus has two different cell ends. It can stick to a surface with its sticky stalk on one end and have flagella on the other.

This bacterium also starts cell division in the middle like what we discussed above. However, the new daughter cells are now different: one is still glued to the surface and the other one has flagella and can swim away.

Also, the bacterium Helicobacter pylori with its helical shape can never really find its perfect middle. Hence, the Z-ring forms somewhere inside the bacterium and its daughter cells always have different sizes.

And then there are funny bacteria that decided they don’t even need to divide in the middle. Bacteria like Gemmatimonas aurantiaca grow “budding” daughter cells out of their own parent cells. However, researchers don’t understand yet why this bacterium chooses to divide in this asymmetric way.

Another way of asymmetric cell division happens in the bacterium Bacillus subtilis when it produces spores. During the sporulation process, the spore daughter cell grows within the mother cell. In the end, the mother cell bursts to release the spore into the environment. In this case, only one daughter cell comes out of the division process.

Why and how we want to prevent bacteria from dividing

Since cell division is an essential mechanism for bacteria, nature also found ways to inhibit it. Many antibiotics or toxins inhibit the production of cell envelope material or of the Z-ring. Like this, bacteria cannot divide anymore; they cannot grow and die.

However, we also know that some bacteria can find ways around the toxicities of antibiotics or toxins and become resistant to them. Hence, by better understanding how the whole mechanism works, researchers can hopefully find new ways to interfere with bacterial growth and find new weapons in the fight against antimicrobial resistance.

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Bacterialworld - A blog about bacteria: from scientific studies to vivid stories about the fascinating bacterial world

They don’t have eyes to see what is going on.

Neither do they have ears to hear a foe approaching.

And yet they seem to know exactly what is happening around them.

How is that possible?

In other articles, we already looked at different mechanisms of how bacteria sense their environment. And we learned about various ways bacteria use to know what is going on around them.

Here, we will look at another one of these mechanisms. A mechanism in which bacteria destroy proteins to understand the environment and adapt to it.

But before we can look at why bacteria destroy proteins, we first need to understand how bacteria produce proteins.

Bacteria need proteins to produce proteins

Every living cell, like a bacterial cell or a human cell, contains DNA. And the DNA contains many different sections, which are genes. These genes are the templates for ALL proteins that a cell can produce.

A cellular machine called the polymerase (bright blue in the figure below) recognizes the start of a gene (yellow), before it transcribes this gene into a string of mRNA (grey). Next, a ribosome reads the mRNA fragment and translates it into a protein (yellow).

This is how every living cell produces proteins from DNA.

Now, we will focus on the first step: when the polymerase recognizes the start of a gene.

Bacteria need proteins to regulate protein production

When you think about it, bacteria do not always need all genes and all proteins. Just as you don’t need an umbrella when it is sunny outside, but it is always good to keep it handy. Similarly, bacteria have heaps of genes on that long string of DNA and they need some of them only under certain circumstances.

For this, all living cells have regulators. These regulators make sure that the polymerase only produces mRNA from genes that are required at a specific time point.

And these regulators come in two forms: activators and repressors.

Activators activate genes

Sometimes, the polymerase cannot recognize a specific gene on its own. This is when the polymerase needs an activator (green). 

An activator is a protein that binds to a specific gene only when needed. This attracts the polymerase to this gene so that it produces mRNA from that gene. Like that, an activator ensures that bacteria only produce certain proteins when needed.

This means something else needs to activate the activator at a specific time point. And while some activators are activated by specific systems as explained in How bacteria sense their environment, sometimes protein-destroying systems are involved. More about that below.

Repressors deactivate genes

Repressors (dark blue) do exactly the opposite of activators. These proteins bind specific genes right at the start. This blocks the polymerase from binding the start of that gene and from producing mRNA.

But when the bacterium needs a specific protein, the polymerase has to recognize and bind that specific gene. At that point, the bacterium has to get rid of the repressor.

So, let’s have a look at how bacteria gain access to genes that need activators or are blocked by repressors.

Bacteria destroy proteins to understand the environment

The environment constantly changes for a bacterium. So, all the time, a bacterium needs to produce certain proteins to handle these new situations. Just as you take your umbrella when it is raining suddenly.

This is when the bacterium needs the polymerase to recognize a specific gene to make mRNA from it.

To get rid of a repressor or to activate an activator when needed, bacteria came up with a simple mechanism: protein destruction.

Yes, to produce proteins, sometimes bacteria destroy proteins.

Proteins that destroy proteins are called proteases and these work like molecular scissors. Proteases cut proteins in at least one specific location. This makes the protein fall apart and become kaput. 

When do bacteria destroy proteins?

Different bacteria developed various mechanisms when to destroy specific proteins. And researchers start to understand more and more about this way of regulation.

So, let’s have a look at a few cool examples of bacteria destroying proteins.

Radiation leads to protein destruction and survival

For example, the fascinating bacterium Deinococcus deserti has genes to cope with radiation and desiccation. However, the bacterium does not need to produce these proteins when there is no radiation or desiccation.

Under these circumstances, the repressor D (dark blue in the figure below) blocks these genes and makes sure the polymerase cannot recognize them.

But as soon as the bacterium is hit with radiation (lightning), the radiation activates the protease M (red). This protease can now bind the repressor D and destroy it. Now, that the repressor does not block the radiation genes anymore, the polymerase can recognize the genes and produce mRNA from them. Now, the ribosome produces proteins (yellow) that cope with the radiation. 

And this is how the bacterium Deinococcus deserti destroys proteins to survive. And yes, this bacterium has the superpowers to withstand radiation and desiccation like no other bacterium.

Antibiotics lead to protein destruction and resistance

In another example, Staphylococcus aureus has a similar mechanism to cope with antibiotics and become resistant. 

In the membrane of this bacterium sits the protease R (red) that is generally inactive. However, when the bacterium meets antibiotics (green molecules), the antibiotics change R. 

Now, the protease falls into the inside of the bacterium and destroys its target protein. This is the repressor I (dark blue), which sits and blocks a certain gene. After protease R destroyed repressor I, this gene is unblocked and the bacterium produces a protein (yellow) that cleaves the antibiotic. 

And this is how Staphylococcus aureus becomes resistant to antibiotics by destroying proteins.

Heat leads to protein destruction and survival

But bacteria do not only destroy repressors. They also use a similar mechanism to activate their activators. 

Generally, to keep an activator inactive, another protein is involved. This is the so-called anti-activator since it captures the activator and inhibits it from functioning. So, for the activator to become active and to bind its specific gene, the anti-activator needs to go. And this is exactly what bacteria do.

For example, in the soil bacterium Bacillus subtilis, the anti-activator Y (dark blue) captures the activator S (green). Plus, Y brings S to the cellular garbage machine (purple) to destroy this protein.

However, as soon as it is getting too hot for the bacterium, Y becomes unstable. So unstable, that it cannot hold S anymore. This means S gets freed, binds its favorite genes and leads the polymerase to them. Now, the bacterium produces proteins (yellow) that help the bacterium to cope with the damage from the heat.

And this is how Bacillus subtilis destroys proteins to cope with heat.

Destroying proteins means bacteria can survive

Here we explored three different ways of how bacteria destroy proteins for their own benefit. Interestingly, the benefit always handles the incoming signal which is often a sign of stress.

Like in Deinococcus deserti, radiation activates protein destruction that leads to protein production. And these new proteins now handle the damage after the radiation attack.

Or in Staphylococcus aureus; antibiotics activate a specific protease that destroys a repressor. Now, the produced proteins are meant to destroy the harmful antibiotics.

So by closing these circles, bacteria found efficient ways of how to read their environment and adapt to it.

Interestingly, most bacteria seem to use similar mechanisms. This means, the better we understand the way most bacteria work, the better chances we have to fight the nasty ones. So we need to keep researching the good bacteria, to understand the bad guys too!

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Bacterialworld - A blog about bacteria: from scientific studies to vivid stories about the fascinating bacterial world

Bacteria become resistant to antibiotics. 

Cancer spreads like never before. 

And a virus determines how we live our lives. 

Why do we need to transport drugs within our bodies?

These three major problems need researchers to develop new drugs, like new antibiotics, efficient chemotherapeutics, or long-lasting vaccines.

But we also need to transport these drugs into our bodies and to a specific location. This could be the site of a bacterial infection or the tumor that we’re trying to kill. 

For this, researchers have been working on new delivery methods to transport drugs to a specific site. And, interestingly, many of these methods are based on bacterial mechanisms. So, we felt it was more than worth discussing some of these mechanisms here with you. This will show you another way of how bacteria can save this planet by transporting drugs within our bodies.

Let’s dig in.

Outer membrane vesicles

In Bacteria firing toxic bubbles, we learned that Gram-negative bacteria can form bubbles of their outer membranes. These bubbles are called outer membrane vesicles and they can be filled with stuff.

And researchers also tried to use these bubbles to deliver drugs.

Luckily, our immune system can recognise and respond to outer membrane vesicles. This means our bodies can produce antibodies against the surface of these outer membrane vesicles. 

Outer membrane vesicles carrying stuff on their surface

For example, researchers made the bacterium Escherichia coli produce outer membrane vesicles. Only the lipids of the vesicles – nothing else. They then gave these outer membrane vesicles to mice. These outer membrane vesicles were not dangerous and the mice did not produce antibodies against them.

Then the researchers engineered the vesicles. Between the lipids, the vesicles now carried proteins from the pathogenic bacterium Acinetobacter baumanni. Hence, the protein becomes a so-called antigen. This means, that the mice produced antibodies against the antigen. This made them immune against an Acinetobacter baumanni infection. 

This is an option of how to transport antigens into our body to make us immune against different pathogens.

Outer membrane vesicle bubbles filled with stuff

Another way of using bubbles from bacteria to transport drugs is by filling them with stuff. 

For this, the outer membrane vesicle carries a specific protein. This protein fits like a key to a lock of a certain cell type. Like this, the outer membrane vesicle can dock onto a specific human cell and interact with it. 

Just as you can see in the picture above how outer membrane vesicles are formed, this mechanism can also work the other way around. An outer membrane vesicle can “melt” into a human cell. Then, the content of the outer membrane vesicle flows into the human cell. 

For example, researchers engineered outer membrane vesicles and filled them with a chemotherapeutic. This outer membrane vesicle then specifically melted with cancer cells and shed their content into these. This did not completely kill the tumour but inhibited its growth.

Researchers also developed new vaccines that have DNA or RNA inside these lipid membranes. Read more about vaccines made by bacteria.

As exciting as this mechanism sounds at the moment, it still requires more research to fully understand how we could use outer membrane vesicles as drug-delivering vehicles.

Magnetosomes – bubbles following a magnetic force

Magnetosomes are similar to outer membrane vesicles, as they are bubbles made of a lipid membrane. But in How bacteria read and follow the Earth’s magnetic field, we learned that magnetosomes also have iron-clusters that make them magnetic.

Researchers have the idea to guide magnetosomes with a magnet to a specific location in our bodies. Like this, magnetosomes can go deep into tumour tissue and work their magic there.

Now, similarly to outer membrane vesicles, magnetosomes can be filled with drugs like antibiotics or chemotherapeutics. These drugs are then shed into tumour cells or into the surrounding of tumour cells. 

So far, researchers showed this method in mice. They filled magnetosomes with a vaccine against a tumour, gave them to the mice and held a magnet right next to the tumour. This treatment protected the mice from the tumour and could be used at some point in the clinic. 

Bacterial ghosts – a shell of a dead bacterium

Ghosts of bacteria in your body? That is certainly a science fiction idea.

For this, researchers grow bacteria in the lab and engineer them to produce a protein of interest. This could be for example an antigen that will trigger an immune response in the human body. 

When the bacteria are fully grown, researchers trigger them to produce massive tunnels in their outer membrane. All the content of the bacterial cell will flow out into the surrounding. This means, the bacterium itself is dead and cannot grow anymore. But the bacterial envelope with the antigen is still stable. 

Studies showed that bacterial ghosts with antigens triggered antibody production in rabbits.

In another study, researchers filled the bacterial ghosts with anti-cancer drugs. Fortunately, the bacterial ghosts release the drugs very slowly. Like this, the drug is administered over a long time and is thus more efficient. However, researchers did these basic experiments only on cell lines so far. Hence, a lot more research is required to better understand this mechanism of drug delivery.

Living bacteria to transport drugs

Transporting drugs in the body using living bacteria sounds pretty challenging. But researchers know how to engineer strains that have no damaging effects on our bodies and our immune system. 

Using living bacteria to transport drugs in the body even has many advantages.

Bacteria are attracted by certain chemicals

Bacteria do chemotaxis which means they are attracted by certain chemicals or molecules. 

For example, some bacteria are attracted by areas with low or no oxygen at all. Cancer tissue generally lacks oxygen and the surrounding tissue has very low oxygen concentrations.

Hence, some bacteria are already directly attracted by tumours or cancer tissue.

Also, researchers are trying to engineer bacteria that are attracted to other chemicals. For example, they improve chemotaxis in some bacterial strains. And now these bacteria are more efficient in recognising certain molecules within tumour tissue.

Bacteria move with their flagella

After being attracted by a certain molecule, bacteria actively swim towards this molecule. For this, they use their flagella and pili. 

Hence, this swimming behaviour brings them efficiently to the site of infection.

Bacteria produce drugs on the spot

Bacteria are drug production machines. 

Generally, researchers engineer bacteria in a way that they start producing drugs only when they reach a specific location.

Like this, bacteria produce the right drug at the right time and the right location. 

And they can even produce multiple different drugs. How efficient!

Bacterial hybrid delivery systems – Microbots as the future?

Using a hybrid system between an engineered bacterium and a non-living unit sounds a lot like science fiction. These systems are even called microbots or bactobots. But also here, they have only been tested in the lab, and no studies on humans were done yet (at least to my knowledge!).

A microbot consists of a bacterium that does chemotaxis. So, they could be attracted to tumours or cancer tissue.

And this bacterium carries a nanoparticle that is filled with a drug. Like this, the bacterium steers the particle, and thus the drug, to the place of infection. Here, it can release the nanoparticle, which can now work its magic.

So far, researchers showed in a preliminary study in mice, that bacteria can successfully deliver nanoparticles covered with DNA into specific organs.

However, there are still so many obstacles to consider. But it certainly sounds like a promising and very efficient science-fiction idea.

Bacteria and their organelles can transport drugs within our bodies

Here, I showed you some ideas of how researchers are trying to use bacteria or their organelles to transport drugs within our bodies.

We looked at “bacterial organs” like outer membrane vesicles or magnetosomes. These could carry drugs and deliver them to certain body tissue.

We then discussed how researchers are trying to better understand bacterial ghosts to use them as drug vehicles.

And we explored living bacteria and why researchers think they can use them to transport drugs within our bodies.

Microbots, however, sound like science fiction so far. But, who knows, maybe at some point, we will eat a bacterium that carries a nanoparticle filled with drugs.

I hope we could yet again show you a fantastic way of how bacteria can save our medical problems and thus our planet. So, now is the time to lose the fear of bacteria and believe in them. 

Together with bacteria, we can save this planet.

The post Of microbots and bacterial ghosts – How bacteria could transport drugs within our bodies appeared first on Bacterialworld.
Bacterialworld - A blog about bacteria: from scientific studies to vivid stories about the fascinating bacterial world

Phages are basically genomic information – DNA or RNA – within a lipid-protein shell. Distributing their DNA or RNA into as many hosts as possible allows the phages to survive. They then reprogram the host to produce more phages packed with more phage DNA or RNA.

These newly produced phages then trigger the host to release themselves which can even kill the bacterium. With the release, the phages are spread further into the surrounding until they encounter another host and the cycle begins again.

Of phages and bacteria

Many different bacteriophages exist that specifically infect certain bacteria. So, just as their hosts differ, the phages differ as well. They come in different shapes, sizes and reproductive mechanisms.

Some phages have very simple shapes as in the picture below. Here, we will focus on the filamentous phages that can be even longer than the host bacterium itself.

Filamentous phages are very common in bacteria and they also have a special ability: They program the bacteria in a way that bacteria do not always produce the phage. They control the bacterium and wait until the right moment comes for them to be produced.

This means that these bacteria have DNA of the phages inside their own DNA. And only when the phage DNA is activated, the bacteria actually produce the phages. Until then, the phage is a so-called silent phage within the bacterium.

Let me be your phage

One bacterium that is infected with a silent phage is the pathogenic bacterium Pseudomonas aeruginosa. Within its genome, Pseudomonas aeruginosa contains the DNA for the filamentous Pf4 phage. However, it only produces this phage when the bacteria live in a biofilm community.

So, it seemed that the phages must somehow help the bacteria in the biofilm. As a new study found these phages actually help the bacterium become more resistant to antibiotics and chemical and toxic substances inside the biofilm.

But the way the phages achieve that is a fantastic antibiotic resistance mechanism that was not known before. To learn about the strategy, researchers took images with the microscope of the Pf4 filamentous phage. And they found these long phage filaments.

I wrap around you

While these structures were pretty impressive, they didn’t explain how the phages would actually behave within the biofilm together with Pseudomonas aeruginosa.

So, the researchers added some artificial biofilm from the bacterium to the phages. They then looked at the phages again in the microscope and they saw that the phage assembled and formed ordered filaments. These looked like highly organised nets of phages.

I protect you

The researchers then wanted to see how the bacteria could fit into these nets. So, they took images of the phages together with the bacteria. And they saw that the phages form their nets close to the bacterial cells just as in the picture below.

It seemed that the phage nets wrapped closely around the bacterial cells. Like this, the phages would form a droplet shape around the bacterial cell and separate it from the surrounding.

And these droplets are the foundation for the resistance to antibiotics of the bacteria. When researchers added different antibiotics to the phage-bacteria-droplets, the bacteria survived.

On the contrary, the bacteria on their own were dying from the antibiotic attack.

This means, that the phage net works as a wall to protect the encapsulated bacterium from toxic molecules in the surrounding. This is a completely new and remarkable mechanism of bacteria to protect themselves from environmental dangers. And they use their very own phages to do that!

It seems that another race against antimicrobial resistance just started…

And then I start again

Let’s put it all together and have a look at the life cycle of these phages:

Pseudomonas aeruginosa carries genes for the Pf4 phage in its genome and only activates them when it grows within a biofilm. At this moment, Pseudomonas produces both biofilm material and the Pf4 phage. These released phages then form nets around the bacterial cells. With this net, the phages protect bacteria from antibiotics and other toxic substances.

So, it seems that phages protect their own hosts from environmental dangers. After having hijacked the bacteria’s cell for their own production, it’s actually a pretty nice thing to do.

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Bacterialworld - A blog about bacteria: from scientific studies to vivid stories about the fascinating bacterial world

When you look at a bacterium, you see that it has no eyes to see, no ears to hear and no nose to smell. So, how do bacteria know where they are and what is happening around them?

Bacteria use some simple but highly efficient systems to make sense of their environment. Here, we will look at two of these systems.

Bacteria use complex systems to sense their environment

When we talk of the environment of a bacterium, we mean any kind of condition that a bacterium might encounter in its daily life. This includes temperature, pH, presence or absence of a nutrient, oxygen levels or the presence of certain antibiotics…

And bacteria need to know about the state of these conditions. They need to know how warm or cold it is, where the food is or if they are close to deadly antibiotics. Once they sensed this condition as a so-called signal, they need to respond to it.

This is why scientists called these systems response regulator systems. Bacteria use them to regulate their response to a specific signal.

The one-component system

The simplest of these systems is the ‘one component system‘ as this includes only one protein. This protein has two parts, or modules. One module is the sensor module (bright green in the picture below) which senses or measures a certain signal within the cell. The second module is the response module (dark green) which responds in a specific way to the measured signal. 

The two modules are in close contact with each other. Thus, the response module knows exactly what the sensory module measures and how it is supposed to react. 

In most cases, the sensory module measures the presence or absence of a certain molecule, for example, oxygen or iron. This happens because the sensory module has a very high binding affinity for this molecule.

For example, if oxygen is present within the bacterial cell, it binds to the sensory module. When oxygen is not bound to the sensory module, it has a slightly different structure. In this case, the response module reacts by binding to another response module of another one-component system.

Now, this double protein can bind to bacterial DNA at specific positions. It binds right next to a certain gene to turn this gene on so it can produce specific proteins. These proteins will now help the cell deal with the lack of oxygen.

Like this, the response module ensures that the cell gets the right set of proteins that are needed in this specific situation.

Okay, but this system only measures conditions within the cell. How does a bacterium know what is going on on the outside? 

The two-component system

In this case, the sensory module and the response module are located within two separate proteins. These are the sensor protein and the response protein. Since two proteins are involved in this system, scientists call it the ‘two-component system‘.

Here, the sensor protein has two parts or modules and sits in the bacterial cell membrane. The sensor module is similar to the module in the ‘one-component system’ that we discussed above. The second module has an enzymatic activity (orange in the figure below).

The response protein also has two modules and lives inside the bacterial cell. The receiver module (red) waits for specific interactions with the sensor protein. Interestingly, the second module, the response module, is the same as in the ‘one-component systems’. 

Two-component systems sense signals in the environment

Because the sensor module sits in the bacterial cell membrane, it can sense signals inside or close to the membrane. For example, certain antibiotics damage the cell membrane. Bacteria measure or sense such membrane damage with specific sensory modules. 

Other sensory modules can measure the temperature within a bacterium. The membranes of bacteria are made of fatty acids and you know how the consistency of fat changes when the temperature changes? Similarly, with rising temperatures, the membrane becomes more fluid. On the contrary, at low temperatures, it is more rigid. Interestingly, sensory modules act like thermometers and measure the fluidity of the cell membrane. 

Once a certain signal activates the sensor module in the membrane, its enzymatic module also gets activated. The enzymatic module can then interact with the receiver module from the response protein and adds a little molecule (P) to the receiver.

This addition changes the structure of the response protein. Now, the response module can bind to another response module, similar to what happens in the ‘one-component system’.

Hence, the response itself is similar. Bacteria produce proteins that cope with the detected signal. One example is dealing with changing temperature or getting rid of antibiotics.

The two-component system is also part of the chemotaxis system which controls the movement of bacteria towards nutrients.

Bacteria know how to adapt to the changing environment

In all, bacteria found amazingly simple but efficient ways to sense and know what is going on in their environment. Using these systems, they know exactly how to deal with the changes based on the information they receive. This simple trait, in my opinion, makes them super smart.

Takeaway message from this article 

• Bacteria sense their environment and couple it directly to a specific response
• Signals can derive from within the bacterium or outside of the cell
• The response helps the bacterium to adapt to the new environmental conditions 

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Bacterialworld - A blog about bacteria: from scientific studies to vivid stories about the fascinating bacterial world

And this process is very interesting to researchers. It tells them how bacteria move in the environment, advance their populations and evolve in general. So, here we explain one mechanism of how bacteria break biofilms.

The bacterium Desulfovibrius vulgaris likes water pipes

As you might know, bacteria are basically everywhere. And they like to build their biofilm houses on pretty much any surface they can find. Be it in or on our bodies or somewhere in nature and the environment.

For example, the bacterium Desulfovibrio vulgaris likes to live on metallic surfaces in the soil. These could be water systems or pipelines that are wet and warm.

Here, the bacterium builds its biofilm house to be protected from the surrounding. Now, Desulfovibrio vulgaris can use the metal from the pipe to gain energy, so it “breathes” the metal. But this metabolic activity leads to the metal pipes corroding or rusting.

And when these metal pipes start corroding, they stop functioning properly which can lead to some serious health issues. So, researchers decided to look into how these bacteria build and break their biofilms.

Bacteria build and break biofilms

The researchers looked at the genes of Desulfovibrio vulgaris with bioinformatic tools. And they found some genes that the bacterium uses to produce less biofilm. Researchers already know some of these genes from other bacteria. Here, these genes also prevented the bacteria from producing a lot of biofilm.

So, the researchers decided on one of these genes and looked at them in more detail. They found that the gene produced a specific enzyme, which is a protein with a special activity.

And in this case, the enzyme’s activity was that it works like a scissor and breaks the biofilms of Desulfovibrio vulgaris. But the researchers also found that this scissor can break the biofilms of other bacteria.

Scientists have always tried to find some kinds of scissors in bacteria that can break biofilms. However, they usually focused on biofilms formed by bacteria in hospital settings. Now, they finally found a new pair of such scissors made by bacteria that live in the environment.

Why do bacteria produce scissors?

Do they not like living in their biofilm houses?

To answer this question, we need to understand that the bacterial biofilm lifestyle works as a cycle. Bacteria build biofilms and use them as houses. As soon as nutrients are scarce or there are too many bacteria within a biofilm, some bacteria break the biofilms to cut themselves loose.

For this, bacteria need to break down parts of their biofilm houses for which they use their special scissors. After cutting themselves free from the biofilm, they start swimming and looking for a new place to live. Once they found it, they will settle down and build a new biofilm house.

By discovering these new kinds of scissors, scientists now have novel tools to combat bacterial biofilms. These tools could inhibit bacterial biofilms in many different settings like the environment or in hospitals.

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Bacterialworld - A blog about bacteria: from scientific studies to vivid stories about the fascinating bacterial world

How does this bacterium make sure it won’t be disturbed in its new quiet environment? Easy – it builds a house to protect itself and its siblings.

But a bacterial house is a special one – we call it a bacterial biofilm. And bacteria form a biofilm when they want to protect themselves from their surrounding, form communities and grow and reproduce.

Let’s read on to find out what these bacterial houses are and how they build them.

Why do bacteria form a biofilm?

Just like you need a roof over your head to protect yourself from the outside weather, bacteria form a biofilm that works like a house. And they build these houses from scratch.

A bacterial biofilm has protecting walls and a roof around it. These barriers defend them from all sorts of stresses of chemical or mechanical nature.

And there are so many advantages for bacteria to live in such a house:

• Most antibiotics cannot penetrate biofilm so that bacteria are safe inside.
• Bacteria keep their own nutrients and water and oxygen within the biofilm.
• In the case of desiccation or starvation, they can survive inside.
• Immune cells cannot break through a biofilm, hence bacteria inside are protected from the host immune system. 

So, basically, a biofilm is the master accommodation for bacteria. 

Where do bacteria form a biofilm?

Biofilm is the stuff that you can feel on your teeth in the morning after you woke up. But don’t worry, you easily brush it off your teeth. 

Biofilm is the gloomy stuff that grows on your kitchen sponge and it is the crust in your kitchen sink if you haven’t cleaned it for a while.

Some bacteria can form a biofilm on contact lenses, which can lead to eye infections.

Unfortunately, bacterial biofilms are also one of the major burdens in hospital settings. Here, bacteria form biofilms on medical devices like catheters, joint replacements, implants or pacemakers.

Researchers even found microbial biofilms in 3.2 million-year-old fossils from volcanoes.  

So, generally, bacteria can form a biofilm on any surface.

What does a microbial biofilm consist of?

Many microbes and especially bacteria can form a biofilm. And dependent on the microbial and bacterial species, the biofilm can have a different colour, thickness and texture. 

Generally, biofilms consist of bacterial cells (either only one species or many different ones), as well as other microbes as for example viruses or phages. All these microbes inside the biofilm talk to each other and communicate.

Inside the biofilm, bacteria glue themselves together with so-called extra-polymeric substances. These are big molecules that bacteria produce and excrete.

These extra-polymeric substances are proteins, lipids, sugar molecules or polysaccharides and DNA. And these substances give the biofilm its gloomy or slimy texture.

Interestingly, each microbe and bacterium produces a slightly different kind of polysaccharide. And each of these polysaccharides has slightly different chemical properties. This makes the texture of biofilms from different bacteria also slightly different.

Within the biofilm, bacteria can store everything, for example, metal ions bound to DNA, nutrients like sugar, bacteriophages, oxygen… And bacteriophages even protect the bacteria inside the biofilm.

How do bacteria decide to form a biofilm?

This is an important question scientists are currently trying to understand. As soon as we understand how bacteria regulate biofilm formation, we might be able to develop drugs that prevent bacteria from biofilm formation. 

There is a general model of how bacteria form biofilm.

The general idea is that a few bacteria attach to a surface. For this, they use special adhesion proteins that help stick to the surface.

Now, bacteria want to settle down so that they do not need to move anymore. This is why they stop all movement mechanisms like swimming.

As mentioned already, inside the biofilm, bacteria talk to each other. Like this, they know when they are many together and they can start producing these extra-polymeric substances. By excreting them, bacteria get glued to each other. This helps them completely encapsulate themselves with this hydrogel. 

Interestingly, once in a while, a bacterium spontaneously explodes. Then, the other bacteria use the cellular content (so all the DNA and proteins and lipids) of the dead bacterium to form more biofilm.

Inside such a so-called mature biofilm, bacteria happily grow and divide inside.

However, as soon as nutrients become scarce inside the biofilm, the bacteria need to find a new place to live. Then they will start producing scissors to break the biofilm. And when they activate their swimming and motility motors they can detach from the biofilm towards a new place where they start all over again.

How do we research bacterial biofilms?

This is actually pretty easy, as there are many different stains that specifically bind to bacterial biofilm and make them visible. In the picture below you can see two examples.

These are two different stains that visualise bacterial biofilms. With the stain crystal violet, we can see a purple ring of biofilm on plastic and with congo red, we can visualise the structure of a biofilm.

In the above picture, in the left column (PAK) is a biofilm of the bacterium Pseudomonas aeruginosa. This one does not make much biofilm because you can barely see any violet or red stain. The other two columns are different mutants that produce more biofilm. These biofilms you can recognise by the strong violet or red colours.

With these experiments, researchers can understand under which conditions bacteria form more or less biofilm or whether their texture changes. This will eventually help us get a clearer picture of the fascinating life of bacteria and how to counteract them.

We still don’t understand biofilms very well. And so far we know that some enzymes exist that break a biofilm apart. However, the big goal would be to prevent bacteria from forming biofilms in the first place.

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Bacterialworld - A blog about bacteria: from scientific studies to vivid stories about the fascinating bacterial world

But what does it actually mean for a bacterium to be resistant to an antibiotic? What are the mechanisms behind antimicrobial resistance? And what does a resistant bacterium do once it got hit with an antibiotic?

Read on to find out the answers and learn about the basics of antimicrobial resistance mechanisms.

What does antimicrobial resistant mean?

Let’s start by looking at what an antibiotic actually is and how it works.

An antibiotic is a molecule that is supposed to stop other microbes from growing. Microbes and especially bacteria produce antibiotics to fight off other microbial foes. Some bacteria even use antibiotics to protect their hosts from other microbial intruders.

Over the years, we learned to use antibiotics as well to kill microbes like bacteria and fungi. For example, when you have a bacterial or fungal infection, you likely had to take some antibiotics. But antibiotics are useless against viruses, so we cannot use them for viral infections.

When an antibiotic hits a bacterium, the molecule binds its so-called target. This is usually an essential protein within the bacterium. And binding this target prevents it from working properly. But the functioning of the protein is essential for the bacterium, it cannot grow anymore and eventually dies.

Now, there are two options: the antibiotic has such a target within the bacterium and can stop this target from working. This kills the bacterium, which is hence called antibiotic sensitive. If however, an antibiotic does not have an effect on a bacterium, the bacterium is called antibiotic-resistant.

But where do these antimicrobial resistance mechanisms come from? How does a bacterium become resistant to a drug?

Where do antimicrobial resistance mechanisms come from?

Antimicrobial resistance mechanisms have two major sources.

An intrinsic resistance means that a bacterium is naturally resistant to a specific antibiotic. It has these antimicrobial resistance mechanisms from the day it was born.

For example, some antibiotics target specific components within a bacterial cell. This could be the production machinery of the membrane of the bacterium. But then, we know that the membranes of Gram-positive bacteria and Gram-negative bacteria are different. And some antibiotics only work against one of them. So, some bacteria are resistant to certain antibiotics because they have different machineries that produce the membranes.

On the other hand, there are acquired resistances. This is when a bacterium gained or acquired that resistance during its lifetime. This usually happens when bacteria mutate.

Another possibility is that a bacterium takes up DNA from another resistant bacterium. Then the bacterium also gains the superpower to fight off the antibiotic.

But what actually happens with the antibiotic in a resistant bacterium?

What are antimicrobial resistance mechanisms?

As we said, antibiotics can look and work differently. Hence, bacteria worked out different mechanisms to get rid of the harmful molecule. Here, we will look at the best-understood examples of antimicrobial resistance mechanisms.

Blocking the antibiotic from entering

All bacteria produce transporters that import stuff from the outside into the cell. Some of these transporters also import antibiotics. And often a bacterium realises that antibiotics enter the cell via a specific transporter. In this case, the bacterium decides to produce less of this transporter.

Another possibility is that the bacterium changes the transporter. It might still transport its normal substrate but not the antibiotic anymore. With this, the bacterium makes sure that the antibiotic never actually enters the cell. 

Getting rid of the antibiotic

As soon as an antibiotic entered the cell, bacteria can also get rid of it.

For this, bacteria produce efflux pumps. These generally export all sorts of cellular waste and some of these can also export antibiotics. When a bacterium realises that there are antibiotics inside the cell, it produces a lot of these efflux pumps. With this, the bacterium gets rid of the incoming antibiotics quickly.

Changing the antibiotic target

Within the bacterium, the antibiotic binds to its specific target and prevents it from working. However, bacteria can change or mutate this target so that the molecule cannot bind to it anymore. This makes the antibiotic useless.

Yet, the function of the target is usually essential for the bacterium’s survival. So, when changing the target, the bacterium needs to make sure to only prevent antibiotic binding and that the target itself still works. 

Inactivating the antibiotic

Bacteria also found ways to get rid of the molecule by breaking them apart. For this, they produce proteins that completely break the antibiotic or change it slightly. This stops the antibiotic from binding to its target and the antibiotic is useless.

Unfortunately, bacteria have many different proteins to break or change antibiotics. And researchers keep finding more and more of them making it harder for us to fight off resistant bugs.

Covering in biofilm

Some bacteria have the ability to build a so-called biofilm, which is basically a lot of slime in which bacteria can live and grow.

This slime is like a house that protects from danger. So, no antibiotic can enter and all bacteria inside this slime house are protected. Building such a biofilm house is more of a general protection strategy. It just happens that it is also very efficient against antibiotic attacks.

The Joker – having many antimicrobial resistance mechanisms

Now you know that there are different resistance mechanisms to fight off antibiotics. But, imagine a bacterium does not only have one of these mechanisms but several of them.

In this case, the bacterium knows how to get rid of many different antibiotics. So, even though we have a lot of antibiotics available, none of them work. And this is what they call a multi-drug resistant bacterium – or superbug – as these are resistant to many different antibiotics.

Antimicrobial resistance mechanisms are serious

And researchers keep finding new ways of how bacteria get rid of antibiotics. For example, a new study found that bacteriophages can protect bacteria from antibiotics in a completely new mechanism.

This is a serious problem as you can imagine. If we do not have any more drugs to fight bacteria, they will just keep making us sick. This will eventually lead to more and more deaths caused by bacterial infections.

And this is why research is so important. One major challenge for scientists right now is to find alternative anti-microbial drugs to which bacteria cannot become or hardly become resistant.

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Bacterialworld - A blog about bacteria: from scientific studies to vivid stories about the fascinating bacterial world