Miscellaneous protein synthesis inhibitors

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Miscellaneous protein synthesis inhibitors

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USMLE® Step 2 style questions USMLE

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A 25-year-old woman is brought to the emergency department because of confusion, dyspnea, and cough with yellow sputum. The patient was seen in the clinic last week and diagnosed with a viral upper respiratory tract infection. Past medical history is significant for a prior episode of pneumonia due to methicillin-resistant Staphylococcus aureus. Temperature is 40.1 C (104 F), pulse is 120/min, respirations are 29/min, and blood pressure is 130/60 mmHg. Auscultation of lungs reveals bilateral diffuse rhonchi. Chest x-ray shows bilateral alveolar infiltrates in the midlung fields and several thin-walled cavities. The patient is admitted to the intensive care unit and started on an intravenous antibiotic that inhibits bacterial protein synthesis by binding to the 50S ribosomal subunit to prevent the formation of an initiation complex. Which of the following adverse effects is most likely associated with the long-term use of this medication?

External References

First Aid

2024

2023

2022

2021

Anemia

chloramphenicol p. 189

Aplastic anemia p. 427

chloramphenicol p. 189

Chloramphenicol p. 189

aplastic anemia and p. 249, 427

gray baby syndrome p. 249

mechanism (diagram) p. 184

protein synthesis inhibition p. 188

Gray baby syndrome

chloramphenicol and p. 189, 200, 249

Haemophilus influenzae p. , 140

chloramphenicol p. 189

Haemophilus influenzae type B

chloramphenicol p. 189

Meningitis

chloramphenicol p. 189

Neisseria meningitidis

chloramphenicol p. 189

Rickettsia rickettsii p. , 148

chloramphenicol p. 189

Rocky Mountain spotted fever p. 148

chloramphenicol p. 189

Streptococcus pneumoniae p. , 134

chloramphenicol p. 189

Transcript

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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 a 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.

Summary

Protein synthesis inhibitors are a class of antibiotics which prevent bacterial ribosomes from synthesizing proteins. They include drugs like chloramphenicol, macrolides, lincosamides, and oxazolidinones.

Most of these drugs act on the 50S subunit of the ribosome, but their mechanisms can be very different. For example, oxazolidinones like linezolid stop the initiation complex from forming. Both the macrolides and lincosamides prevent translocation. Chloramphenicol inhibits peptidyl transferase which is the enzyme that creates the peptide bonds.

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)
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