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Miscellaneous cell wall synthesis inhibitors

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What is the MOA of Bacitracin?

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A 16-year-old boy is hospitalized after a dirt-bike accident. While recovering from his injuries, he develops a cellulitis. Culture grows catalase-positive gram-positive cocci. A susceptibility test reveals resistance to penicillinase-resistant penicillins. He is treated with the drug of choice for this infection. Soon after, his mother notices that his face and neck are turning red. His blood pressure drops rapidly.

What is the mechanism of action of the antibiotic that caused this adverse reaction?

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Content Reviewers:

Yifan Xiao, MD

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.

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.

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!

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. 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.

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.

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. One way is to shut them down with beta lactamase inhibitors.

Members of this group include clavulanic acid, tazobactam and sulbactam.

Sources
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