Cell wall synthesis inhibitors: Cephalosporins

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Cell wall synthesis inhibitors: Cephalosporins

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A 27-year-old man comes to the emergency department because of headache, nausea, facial flushing, and abdominal cramps that developed shortly after drinking alcohol with friends at a party. The patient last visited his primary care physician 5 days ago and was started on a new medication. Past medical history is significant for asthma, which is managed adequately by albuterol. The patient has had 2 sexual partners over the past 3 months and uses condoms inconsistently. He occasionally consumes alcohol but does not consume tobacco or illicit substances. Temperature is 37.0°C (98.6°F), blood pressure is 117/75 mmHg, and pulse is 102/min. There is no focal abdominal tenderness on palpation. Side effects of a medication used to treat which of the following conditions is most likely responsible for this patient’s presentation?  

External References

First Aid

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Ceftriaxone

Chlamydia spp. p. 146

Chlamydia trachomatis p. , 729

for gonococci p. 140

for Haemophilus influenzae p. , 140

mechanism and use p. 186

mechanism (diagram) p. 184

meningitis p. 177

meningococci p. 140

prophylaxis p. 194

typhoid fever p. 142

Gonorrhea

ceftriaxone p. 186

Lyme disease p. 144

ceftriaxone p. 186

Meningitis

ceftriaxone p. 186

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Cephalosporins are antibiotics which got their name from a mold known as cephalosporium, from which they were originally extracted.

They belong to the pharmacological group of beta-lactam antibiotics.

What all beta-lactams have in common is a beta-lactam ring in their structure, which gives them their name, and also the mechanism of action - which is the inhibition of cell wall synthesis in bacteria.

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.

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 Comparison of Ceftriaxone and Cefuroxime for the Treatment of Bacterial Meningitis in Children" New England Journal of Medicine (1990)
  7. "Third-generation cephalosporins" Medical Clinics of North America (1995)
  8. "Summary of Ceftaroline Fosamil Clinical Trial Studies and Clinical Safety" Clinical Infectious Diseases (2012)
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