Protein synthesis inhibitors: Tetracyclines

Definitions & Key takeaways

Tetracyclines are a class of antibiotics that inhibit bacterial protein synthesis by binding to the 30s subunit of their ribosomes and preventing tRNA from binding. Tetracyclines are broad-spectrum antibiotics, effective against many common gram-positive and gram-negative bacteria, as well as certain types of anaerobic and atypical bacteria. They are often used to treat respiratory and urinary tract infections, skin and soft tissue infections, and sexually transmitted diseases. Common side effects of tetracyclines include phototoxicity, tinnitus, teeth staining, bone growth delay, nephrotoxicity, and hepatotoxicity.

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Introduction0:00–0:38

Tetracyclines are antimicrobial antibiotics that inhibit bacterial ribosomes which are the organelles that make proteins.
Genes become proteins in two steps: transcription and translation. During transcription, a specific gene on the DNA is “read” and a copy is made called a messenger RNA, which is like a blueprint with instructions on what protein to build.
Translation is also known as protein synthesis, and it’s when organelles called ribosomes assemble the protein from amino acids within the cytoplasm.

Physiology0:38–3:33

Now, prokaryotic cells, like bacteria, have smaller ribosomes than eukaryotic cells, like those found in humans. Bacterial ribosomes are made up of a 50S subunit and a 30S subunit which combine to form a 70S ribosome.
Eukaryotic ribosomes are made up of a 60S and a 40S subunits that form a 80S ribosome. Since these proteins are different, we can created medications that selectively interfere with the bacterial ones.
In both eukaryotic and prokaryotic cells, protein synthesis involves initiation, elongation, and termination. In bacteria, initiation occurs when the 50S and 30S subunits bind to the mRNA sequence to form a ribosome-mRNA complex.
The mRNA serves as a blueprint for the protein that will be synthesized. It’s made up of three nucleotide long sequences, called codons.
Transport RNA, or tRNA, carrying different amino acids can bind to these codons with their matching anticodons. The complete ribosome-mRNA complex has 3 sites where tRNA can enter and bind.
These are called the A, or aminoacyl site, the P, or peptidyl site, and the E, or exit site. Elongation starts when the first tRNA, carrying a formylmethionine amino acid, enters the P site and binds to the start codon.
This causes a conformational change in the ribosome which unlocks the A site for the next tRNA. A process called proofreading occurs here where only tRNAs with the matching anticodon can bind to corresponding mRNA codon.
After the next tRNA binds at the A site, the amino acid detaches from the tRNA in the P site and gets attached to the amino acid in the A site by the enzyme peptidyl transferase.
This step is called transpeptidation because the peptide chain is transferred from the P site tRNA to the A site tRNA. Now, the A site has the newly formed peptide chain dangling from it, while the P site has an empty tRNA with no amino acids.
In the final stage of elongation, the ribosome slides across the mRNA, and the A site sits above a new codon, the tRNAs that was in the A site slides over to the P site, and the tRNA in the P site slides over to the E site.
Now, a new tRNA with the matching anticodon binds, and the process repeats until a long peptide chain, called a protein, is synthesized.
Finally, termination happens when the ribosome comes across a termination codon on the mRNA. There are no tRNA anticodons that can bind to these, so they signal the end of protein synthesis.

Mechanism of action3:33–5:12

Tetracyclines were originally derived from soil-dwelling Streptomyces bacteria. They get their name from their structure, which involves four rings bound together, so “tetra” for four, and “cyclins” for rings.
Tetracyclines bind to the A-site on the 30s subunit of the ribosome which inhibits the binding of tRNAs to the mRNA-ribosome complex, and shuts down protein synthesis before it even begins.
Tetracyclines are divided according to their duration of action. Short acting tetracyclines, like tetracycline itself, have a half life of around 8 hours, and long acting ones like doxycycline and minocycline last for 16 hours or more.
Now, some bacteria developed enzymes that can break down tetracyclines, or they have proteins on their membrane that could pump the medication out.
So, we developed glycylcyclines like tigecycline, which are modified tetracyclines with an extra dimethylglycylamido side chain.
This prevents them from binding to bacterial proteins and enzymes so they can overcome bacterial defense mechanisms. Administration of tetracyclines is usually topical, or peroral, but tigecycline is IV only.
If used perorally, tetracyclines should not be taken with food because they readily bind with magnesium, iron, aluminium, and calcium, and the resulting molecule is then unable to be absorbed.
That is why tetracyclines are not given to patients on iron and calcium supplements, as well as antacids, which can contain aluminium salts.
Tetracyclines are broad spectrum, meaning they can target a wide variety of Gram positive and negative bacterial. They are often used to treat severe acne or community acquired pneumonia.

Indications5:12–6:26

Tetracyclines also tend to accumulate within human cells, which makes them useful for treating intracellular pathogens. Common intracellular bacteria include mycoplasma pneumoniae which causes atypical, or walking pneumonia, and Chlamydia trachomatis which causes chlamydia.
Less common diseases include those transmitted by ticks, like rocky mountain spotted fever from rickettsia species, rabbit fever or tularemia from Francisella tularensis, and Q fever, which is more commonly transmitted by inhaling farm animal fecal particles that contain Coxiella burnetii.
For Lyme disease, which is caused by ticks carrying borrelia burgdorferi, doxycycline is the medication of choice. It can also be given to prevent malaria, which is a parasitic protozoa that infect blood cells and hepatocytes.
Both doxycycline and tigecycline are also effective against MRSA, a notoriously tough bug that resists many common antibiotics.

Side effects & Contraindications6:26–7:17

For side effects, tetracyclines cause phototoxicity, where patients are much more likely to get sunburned, and tinnitus or ringing in the ear.
They can also accumulate in teeth and bones, which cause permanent discoloration of the teeth and a delay in bone growth.
This is particularly important in children under eight years of age and in pregnant or breastfeeding women where these medications are contraindicated.
Metabolic products of tetracycline are nephrotoxic, and can cause Fanconi syndrome where there’s inadequate reabsorption in the proximal renal tubules.
Tetracyclines are also not very shelf-stable, and using them after their expiration date can cause liver failure. Other side effects are nonspecific, and include stomach upsets, diarrhea, and on rare occasions, allergic reactions.
Now, we want to make a simple and fun mnemonic that’ll help you efficiently memorize and retain all these pharm facts! Since we are talking about “cyclins” let’s have a wacky bicycle race.

Memory palace7:17–9:55

Now the short acting medication of this class is tetracycline so let’s have a pair of twins riding a 4 wheeled cycle in last place.
Up ahead, are the long acting medications so we have a minotaur on a bike for minocycline, and a biking doctor for doxycycline.
Pulling ahead of the others is a tiger for tigecycline, who’s riding a heavily modified hang glider bike because it’s a glycylcycline which allows tigecycline to easily glide over bacterial defense mechanism.
For the bugs treated by these medications, let’s use the spectators of the race. First, tetracyclines are commonly used to treat acne, so there’s a teen with a lot of pimples.
His wheelchair bound grandmother is also there with an oxygen mask to represent community acquired pneumonia, which is common in nursing homes.
Next we have the intracellular bugs so let’s rope off an area for these guys. There’s a young hiker who’s also wearing an oxygen mask since walking pneumonia is common in young adults.
He’s standing on a giant clam, which represents chlamydia, to get a better view. Next are the tick transmitted diseases, so let’s have a mountain climber with a red polka dotted shirt, for rocky mountain spotted fever.
He brought his French pet rabbit for rabbit fever which is caused by francisella. His girlfriend is wearing a brunette wig for C.
burnetii, and a shirt with a giant Q on it to represent Q fever. She’s throwing a giant wedge of lime at the doctor since doxycycline is the first line treatment for lyme disease, but the doctor is distracted from the swarms of mosquitoes chasing him which represents malaria.
Finally the doctor is about to run over a poor Mars rover for MRSA, which was already ran over by the tiger, because both medications are effective against it.
For side effect, we can use the referee of the race. He fell asleep in his chair, and his skin is quite sunburned to represent phototoxicity.
In his arms, there’s a crying baby with big yellow teeth and very short arms to help you remember tetracyclines build up in the teeth and bones, and they should not be used by pregnant women or children.
There’s an electric fan on the sleeping ref’s knees for fanconi syndrome. Since the race is almost over, his alarm clock is ringing, which represents tinnitus.
Next to him is his half eaten lunch, which is a plate of rotting liver thats been sitting in the sun too long. This represents the hepatotoxicity caused by expired tetracyclines.
All right, as a quick recap... Tetracyclines are antibiotics that prevent protein synthesis by binding to the 30s subunit of bacterial ribosomes and preventing tRNA from binding.

Review9:55–10:33

They are broad spectrum and are used for treating many common Gram negative and positive bacteria infections. Since they accumulate in our cells, they are very effective against intracellular bacteria like chlamydia.
Side effects of tetracyclines include phototoxicity, tinnitus, teeth staining, bone growth delay, nephrotoxicity, and hepatotoxicity.
It is contraindicated during pregnancy, breastfeeding, and for children under 8. 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.