Miscellaneous cell wall synthesis inhibitors

Definitions & Key takeaways

The inhibition of bacteria's cell wall synthesis is a common and successful strategy for treating a broad range of bacterial infection. The major cell wall synthesis inhibitors currently in use are the beta-lactams (e.g., penicillin and cephalosporins), which block the formation of the peptidoglycan layer, and glycopeptides (vancomycin and teicoplanin), which disrupt assembly of the peptidoglycan precursor lipid II.

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Introduction0:00–0:26

Beta lactam antibiotics, such as penicillins and cephalosporins, have a beta-lactam ring in their structure, which gives them their name.
These medications inhibit cell wall synthesis in bacteria. Unfortunately for us, bacteria are becoming increasingly resilient to beta lactams, so we’ve come up non-beta lactam medications to inhibit cell wall synthesis.
So, our body is made out of eukaryotic cells. Bacterias belong to a different type of cells, called the prokaryotes.

Physiology0:26–2:00

From the outside to inside, they have a slimy capsule made out of polysaccharides. Then, there’s a cell wall in most prokaryotes.
A cell wall is a structural layer, which encapsulates bacteria, and offers structural support and protection, like a suit of armor.
It also offers some filtering capabilities, as not everything can pass freely through it. Finally, on the inside, there’s a pretty standard cell membrane.
Should something happen to this wall, say, if its synthesis mysteriously stopped, its owner’s life expectancy will turn to that of a snowflake in Sahara.
And that’s exactly what we’re hoping to do. Bacterial cell walls are made of a substance called peptidoglycan, or murein.
Peptidoglycan is a very strong, crystal lattice resembling three-dimensional structure, composed out of long using “strands” of amino polysaccharides, running in parallel.
These are made of made out segments of N-acetylglucosamine, or NAG, and N-acetylmuramic acid, or NAM, in an alternating pattern - so, NAG, NAM, NAG, NAM, and so on, like a pearl necklace.
These strands are also cross linked by short, four to five amino acids long, or tetrapeptide chains, protruding from NAM subunits.
Those pentapeptides reach out and link to pentapeptide chains from the neighboring strands, for structural stability, a sub-process known as transpeptidation.
All of this is made possible by enzymes called DD-transpeptidases, that are also better known as penicillin binding proteins, or PBPs.
These enzymes are highly specialized to grab and hold two pentapeptide ends and fuse them together, creating a stable link between the two polysaccharide strands, essentially creating peptidoglycan.
If you imagine the enzyme as a “lock”, then the pentapeptide chain would be a key, so it fits perfectly in, and allows the enzyme to do its work.

Mechanism of Action2:00–2:37

In essence, all beta lactam antibiotics, like the cephalosporins, somewhat resemble the tetrapeptide chains. Inside the bacteria, PBP enzymes will mistakenly bind to the beta lactams antibiotic molecule instead of a tetrapeptide and stick inside the PBP forever, like chewing gum in a keyhole, permanently disabling it.
As more and more of PBPs get disabled, the crosslinking fails to occur, and the wall becomes weak and unstable. If the affected bacteria attempts to divide, their cell wall will collapse, killing them in the process!

Antibiotic Resistance2:37–4:04

Now, some bacteria have developed resistance to beta lactam antibiotics. The most notable is the notorious staphylococcus aureus, which evolved an enzyme called beta lactamases or penicillinases that breaks down the beta lactam ring within the antibiotic, rendering it ineffective.
In response, we started adding beta lactamase inhibitors, such as clavulanic acid, that would binding to beta lactamases and inactivate them, like the gum into the keyhole.
Another approach was to create newer kinds of beta lactam antibiotics like methicillin, which had a large side chain that wouldn’t “fit” into the keyhole of the beta lactamase.
They did work quite well, until some staphylococcus aureus developed PBP site mutations that changed the shape of the keyhole.
So even if beta lactamase enzymes can’t break down these antibiotics, they won’t fit into the PBP enzyme and thus won’t work.
We call these bacteria methicillin resistant staphylococcus aureus, or MRSA. This poses a huge problem, as it makes MRSA virtually untreatable by beta lactam antibiotics.
Now, to overcome these resistances, we have found ways to inhibit cell wall synthesis at multiple stages. We want to make a simple and fun mnemonic that’ll help you efficiently memorize the medications that work on each of these stages.

Memory Palace4:04–4:35

So, first we can use bacteria carrying wheelbarrows for the transport proteins that move NAM and NAG across the cell membrane Next, are the bacterial security guards which represents the beta lactamase enzymes.
They are protecting the bacterial masons which are the PBPs that build the cell wall. Finally we have the wall itself, which is under construction.

Bactoprenol Inhibitors4:35–5:34

Our first class of medication is the bactoprenol inhibitors, such as bacitracin. It works by blocking bactoprenol phosphate, which is the transmembrane transporter embedded within the bacterial cell membrane.
It lets NAM and NAG molecules cross from inside the cell membrane to the outside, where they’re needed for the synthesis of peptidoglycan.
Once the transport protein is inhibited, new peptidoglycan can no longer be made. Bacitracin has a very narrow spectrum and only works against a few gram positive bacteria like Staphylococcus aureus, Staphylococcus epidermidis, and Streptococcus pyogenes - and even then, it only works topically - meaning, it is used to treat skin and eye infections by rubbing it onto the affected area.
They are never to be applied IV or IM, as they are highly nephrotoxic, and can lead to renal failure if used for systemic infections.

Memory Palace5:34–6:01

Back to the mnemonic. For this class of medication, we are attacking bacterial membrane transport proteins represented by the wheelbarrows.
Let’s have a basilisk, representing bacitracin attack them. These bacteria are purple since bacitracin works on common gram positive bacteria that stains purple.
Let’s have it shed its skin because this medication is for topical use only for treating certain skin infections. Next, let’s look at how we can overcome the beta lactamase problem.

Beta Lactamase Inhibitors6:01–6:48

One way is to shut them down with beta lactamase inhibitors. Members of this group include clavulanic acid, tazobactam and sulbactam.
These medications play a supportive role and are given with beta lactams like penicillin. Once inside the bacteria, they bind permanently to the beta lactamase enzymes and disable them, which allows the penicillins to do their work.
However, they are more effective against Gram negative bacteria since Gram positive bacteria like S. aureus often have PBP mutations that render the penicillins ineffective.
These combo medications often have their own names like augmentin, which is a combination of amoxicillin and clavulanic acid.

Memory Palace6:48–7:22

Back to the mnemonic, Let’s look at the bacterial security guards representing the beta lactamases. We have an erupting volcano to represent clavulanic acid, and a police officer with a baton to represent tazobactam and sulbactam.
Together, they are enough to scare away the security guards. Notice some are purple, since Gram negative bacteria stain pink, and the rest are purple for the Gram positive bacteria.
This clears the way for the “penda” with a pen, our symbol for penicillin. Next, are two groups of beta lactam antibiotics that have a slight twist!

Carbapenems7:22–8:49

First are the carbapenems which include imipenem, meropenem, ertapenem and doripenem. They bind to PBPs and inhibit cell wall synthesis just like penicillin.
However, the twist is they possess a modified ring structure so instead of a sulfur atom at position 1, they have a carbon atom.
This tiny change makes the beta lactamases unable to bind to the medication! Carbapenems are considered to be more potent than the beta lactams.
Their spectrum is wider, and they cover most of the Gram positive and Gram negative bacteria as well as anaerobic species.
With the exception of ertapenem, carbapenems are notably useful against acinetobacter species, which cause nosocomial infections like ventilator-associated pneumonia, and pseudomonas aeruginosa, a bacteria so hardcore resilient, it swims laps in hand disinfectant just to wake up.
These medications are only used when other antibiotics fail since they have severe CNS toxicity and could cause seizures.
Imipenem is rapidly broken down in the kidneys by tubular dehydropeptidase. To make things worse, the metabolites are also nephrotoxic.
That’s why it's used with cilastatin, which inhibits the tubular dehydropeptidase. The other beta lactam medication we’ll talk about are the monobactams.

Monobactams8:49–9:29

The only member of the family that’s currently used is aztreonam. Unlike the other beta lactams, their beta lactam ring is not fused to any other ring, and it’s sticking out on its own.
This makes them resistant to beta lactamases, as they can’t fit properly inside them. They are very effective against Gram negative bacteria, like Escherichia coli and Proteus species, as well as the dreaded Pseudomonas aeruginosa, but they are completely ineffective against Gram positive ones.
Aztreonam is well tolerated and have few side effects. Back to the mnemonic.

Memory Palace9:29–11:06

For this scene we have the 2 groups of beta lactams that are directly assaulting the bacteria masons representing the PBPs.
First, coming in from the bottom is a lone amazon warrior for aztreonam. She’s only attacking pink colored masons because it’s effective against Gram negative bacteria only.
She’s also throwing a spear at a Mona Lisa look alike representing pseudomonas. Next, flanking from the top, are the carbapenems which are represented by a squad of carb-rich penne pasta soldiers.
We have them attack second because they are used after other antibiotics have proven ineffective. Leading them is their emperor, representing imipenem.
He's carrying a celery secepter because we need cilastatin to prevent breakdown of the medication in the kidneys. The army is attacking both purple and pink masons since they are effective against both Gram positive and negative bacteria.
One of their main targets is the other Mona Lisa look alike. She’s holding a fish bowl to represent anaerobic bacteria, and a large cinema ticket for acinetobacter, but it’s highly unlikely that she’ll make it to the movies this day.
Now, one of the pasta soldier is shamefully tap dancing away from the Mona Lisa. He represents ertapenem, the only carbapenem with no effect against pseudomonas.
War can be grim, and some of the pasta soldiers are lying on their side, with their head chopped off and twitching. This will help you remember the severe CNS toxicities that could lead to seizures.

Glycopeptides11:06–12:26

The final family of medications is the glycopeptide antibiotics, like vancomycin, telavancin, and teicoplanin. They inhibit cell wall synthesis by latching onto the tetrapeptide chains, prevent them from being linked by the PBP enzyme.
Glycopeptides do not act on the PBP, which allow them to bypass the PBP mutations that make MRSA so resistant to beta lactams.
However, some Staphylococcus aureus evolved to have a D-lactate at the tip of the tetrapeptides so glycopeptides can’t bind to them.
Some of these strains have partial resistance and are called “Vancomycin intermediate S. aureus”, or VISA for short.
Strains with complete resistance are called “Vancomycin resistant S. aureus”, or VRSA.
Glycopeptides are most often used to treat Gram positive bacteria that are resistant to other medications. They can’t be absorbed in the GI tract so they’re typically given via IV when treating systemic infections.
Peroral vancomycin can be given to treat GI infections like Clostridium difficile. Adverse drug reactions include thrombophlebitis, ototoxicity, nephrotoxicity, and so-called “Red Man Syndrome” which is caused by diffuse flushing.

Memory Palace12:26–13:32

Back to the mnemonic. We are now looking at the wall and we have 3 vehicles representing these medications.
There’s a van with a mouse logo for vancomycin, a van with a TV logo for telavancin, and a police- or “cop”- plane for teicoplanin.
Now, these medications act directly on the molecules that make up the cell wall so let’s have them crash into it. The wall itself is purple to represent Gram positive bacteria, and let’s put some barbed wire on it because glycopeptides are used to treat infections that’s resistant to other medications.
Toppling off the wall, there’s a closet for clostridium, and on top of that, is a Mars rover for MRSA. For side effects, let’s use the driver of the van who’s running away from the vehicle.
He's dressed in a red ninja outfit to represent “Red man syndrome”. He’s wearing headphones that’s blasting loud music for ototoxicity, and one of his leg is covered in bulging blue veins for thrombophlebitis.
He’s also holding his injured flank as he hobbles away to help you remember nephrotoxicity. All right, as a quick recap, let’s look at a mind map that’ll help organize the information we covered.

Review13:32–14:35

Multiple families of cell wall synthesis inhibitors are created to combat the ever increasing resistance in bacteria. Bactoprenol inhibitors like bacitracin inhibit the transport proteins that move NAG and NAM units across the cell membrane.
Beta lactamase inhibitors like clavulanic acid are used to disable beta lactamases, and they need to be used in combination with other beta lactams like penicillin.
Carbapenems like imipenem, and monobactams like aztreonam, are beta lactam antibiotics with slightly modified structures.
This makes them impervious to beta lactamase degradation so they can inhibit PBPs. Glycopeptides like vancomycin binding to tetrapeptides that make up the cell wall.
This allows them to bypass bacterial resistance based on PBP mutations. They are mostly used for dealing with highly resistant bacteria such as MRSA.

Mind Map14:35–14:47

But wait, there's more: Here's a mind map with all of the mnemonics from the video. Go ahead and pause the video so you can test yourself to see what you remember.
Stay tuned for the answers at the end.