Miscellaneous cell wall synthesis inhibitors

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Miscellaneous cell wall synthesis inhibitors

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USMLE® Step 2 style questions USMLE

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A 12-year-old boy comes to the emergency department due to wounds on the thighs and palms of the hands after a motor vehicle accident. Past medical history is unremarkable. Temperature is 37.0°C (98.6°F), pulse 80/min, respirations 20/min, blood pressure 105/75 mmHg, and SpO2 is 99% on room air. Physical examination shows several abrasions from ankle to mid-thigh bilaterally and abrasions on both palms. The patient is treated with a topical ointment containing an antibiotic that binds to phospholipids on cell membranes and disrupts the membrane integrity. Which of the following agents did this patient most likely receive?  

External References

First Aid

2024

2023

2022

2021

Bacitracin

Gram-positive antibiotic test p. 132

mechanism p. 184

sensitivity to p. 132, 132

Bacitracin response p. 726

Streptococcus pyogenes (Group A strep) p. 134

bacitracin response p. 726

Transcript

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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!

Summary

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.

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. "Penicillin-Binding Proteins of Gram-Negative Bacteria" Clinical Infectious Diseases (1988)
  5. "Methicillin-resistant Staphylococcus aureus: A consensus review of the microbiology, pathogenesis, and epidemiology with implications for prevention and management" The American Journal of Medicine (1993)
  6. "A systematic review and meta-analysis on the use of prophylactic topical antibiotics for the prevention of uncomplicated wound infections" Infection and Drug Resistance (2018)
  7. "UREIDOPENICILLINS AND BETA-LACTAM/BETA-LACTAMASE INHIBITOR COMBINATIONS" Infectious Disease Clinics of North America (2000)
  8. "Carbapenems" Medical Clinics of North America (1995)
  9. "CEPHALOSPORINS, CARBAPENEMS, AND MONOBACTAMS" Infectious Disease Clinics of North America (2000)
  10. "Therapeutic Monitoring of Vancomycin in Adults" Pharmacotherapy (2009)
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