Miscellaneous protein synthesis inhibitors

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Miscellaneous protein synthesis inhibitors

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Miscellaneous protein synthesis inhibitors

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A 4-year-old girl is brought to her pediatrician because of abdominal cramps and diarrhea for the past two days. The patient's mother noticed that her stools are bloody, contain mucous and are small in volume. She also mentions that 2 other children at her daughter's daycare have similar symptoms. Physical examination shows a young girl in moderate distress with a fever of 39.6°C (103.3°F). Analysis of the patient's stool sample shows polymorphonuclear leukocytes on a methylene blue stain. A complete blood count was obtained and shows 14/mmwhite blood cells. Which of the following is the most appropriate treatment for this patient's condition?

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Protein synthesis inhibitors include many different classes of medications that prevent bacterial ribosomes from synthesizing proteins.

The ones that target the 50S subunit of the ribosome include chloramphenicol, macrolides, lincosamides, and oxazolidinones.

Okay, first, let’s look at how genes become proteins. There’s two steps: transcription and translation.

During transcription, a specific gene on the DNA is “read” and a copy is made called a messenger RNA, or mRNA, 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.

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 subunit that form an 80S ribosome.

Since these proteins are different, we can create medications that selectively interfere with the bacterial ones.

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, also called the initiation 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, on top of which transport RNA, or tRNA, carrying amino acids can bind with their matching anticodon.

The complete ribosome 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 which unlocks the A site for the next tRNA.

The next tRNA binds at the A site, the amino acid detaches from the tRNA in the P site, and a peptide bond is formed by an enzyme called peptidyl transferase between the amino acids in the P and A sites, a process known as transpeptidation.

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 tRNA in the P site slides over to the E site, and the tRNA in the A site slides over to the P site.

The ribosome slides over so the free A site is over the next codon on the mRNA and this process is called translocation.

Next, a new tRNA with the matching anticodon binds, and the process repeats until a long peptide chain called a protein is synthesized.

Okay, so let’s look at some protein synthesis inhibitors. Chloramphenicol is a bit of a loner, and is the single representative in its group.

It works during elongation by inhibiting peptidyl transferase, thus preventing peptide bond formation between new amino acids and the polypeptide chain.

It’s a broad spectrum bacteriostatic medication, meaning it limits the growth of bacteria, rather than eradicating them.

It’s well absorbed both perorally as well as parenterally, and it readily crosses the blood-brain barrier so it could be used to treat bacterial meningitis.

Resistance to chloramphenicol occurs through acetyltransferase enzymes, which add an acetyl group to chloramphenicol to inactivate it.

Chloramphenicol is effective against some strains of Haemophilus influenzae, Neisseria meningitidis, Bacteroides species, and Rickettsia species.

However, due to its severe toxicity, it’s no longer used systemically in most countries with access to safer alternatives.

Nowadays, it’s most commonly used in the form of eye ointments to treat bacterial conjunctivitis.

For the side effects, it’s very toxic to the bone marrow and could kill off the hematopoietic cells, leading to bone marrow suppression.

This will usually lead to aplastic anemia first, followed by a decrease in platelets and leukocytes.

It’s also notoriously teratogenic, as it readily crosses the placenta, so it should not be given to pregnant people or newborns.

This is because infants lack the hepatic enzyme glucuronosyl transferase which normally metabolizes chloramphenicol.

When this medication accumulates, it causes “gray baby syndrome”, where the infant is anemic and cyanotic, where the skin is a pale, or grayish color, and it can lead to cardiovascular collapse.

Chloramphenicol also inhibits the hepatic enzymes in the cytochrome p450 family.

These enzymes break down many other drugs, like warfarin, so when they are inhibited, it increases the action of those medications.

Next, let’s look at the macrolide antibiotics which include erythromycin, azithromycin, and clarithromycin.

They work by binding to the 50S subunit of the ribosome, and block translocation, so the ribosome can’t slide to the next codon on the mRNA.

They can be administered perorally as well as parenterally.

Macrolides are broad spectrum bacteriostatic medications effective against Gram positive and Gram negative bacteria alike.

Specifically, they are used as the first line therapy for Bartonella pertussis, which causes whooping cough.

Sources
  1. "Katzung & Trevor's Pharmacology Examination and Board Review,12th Edition" McGraw-Hill Education / Medical (2018)
  2. "Rang and Dale's Pharmacology" Elsevier (2019)
  3. "Goodman and Gilman's The Pharmacological Basis of Therapeutics, 13th Edition" McGraw-Hill Education / Medical (2017)
  4. "Chloramphenicol: A Review" Pediatrics in Review (2004)
  5. "Clarithromycin: Review of a New Macrolide Antibiotic with Improved Microbiologic Spectrum and Favorable Pharmacokinetic and Adverse Effect Profiles" Annals of Pharmacotherapy (1992)
  6. "New Macrolide Antibiotics: Azithromycin and Clarithromycin" Annals of Internal Medicine (1992)
  7. "Macrolides and ketolides: azithromycin, clarithromycin, telithromycin" Infectious Disease Clinics of North America (2004)
  8. "Enhancement of opsonophagocytosis of Bacteroides spp. by clindamycin in subinhibitory concentrations" Journal of Antimicrobial Chemotherapy (1989)
  9. "Linezolid versus Vancomycin for the Treatment of Methicillin‐ResistantStaphylococcus aureusInfections" Clinical Infectious Diseases (2002)