Cell wall synthesis inhibitors: Penicillins

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Cell wall synthesis inhibitors: Penicillins

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Bacterial structure and functions
Staphylococcus epidermidis
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Rickettsia rickettsii (Rocky Mountain spotted fever) and other Rickettsia species
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Protein synthesis inhibitors: Aminoglycosides
Antimetabolites: Sulfonamides and trimethoprim
Antituberculosis medications
Miscellaneous cell wall synthesis inhibitors
Protein synthesis inhibitors: Tetracyclines
Cell wall synthesis inhibitors: Penicillins
Miscellaneous protein synthesis inhibitors
Cell wall synthesis inhibitors: Cephalosporins
DNA synthesis inhibitors: Metronidazole
DNA synthesis inhibitors: Fluoroquinolones
Mechanisms of antibiotic resistance

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Cell wall synthesis inhibitors: Penicillins

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A 40-year-old man comes to the office for the evaluation of a skin rash. It began a week ago on his trunk and has spread to his entire body now. He also reports low-grade fever, malaise, sore throat, and headache. The rest of the review of systems is unremarkable. He has had three female sexual partners over the past year. Past medical history is significant for type II diabetes mellitus managed with lifestyle modifications. Temperature is 37.2°C (99 F), pulse is 80/min, respirations are 17/min and blood pressure is 130/70 mm Hg. Physical examination shows a full-body maculopapular rash as shown below. Several gray, mucosal patches are seen in the mouth. Cervical, axillary and epitrochlear lymphadenopathy is present. HIV testing is negative. The patient is administered an intramuscular dose of penicillin G and sent home. He later presents to the emergency department three hours later with a worsening rash, muscle pain, rigors, and chills. His temperature is now 38.3°C (100.9 F), pulse is 80/min, respirations are 20/min and blood pressure is 100/60 mm Hg. Which of the following is the most likely cause of this patient’s current symptoms?


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External References

First Aid

2024

2023

2022

2021

Amoxicillin

clinical use p. 185

Haemophilus influenzae p. , 140

Helicobacter pylori p. , 144

Lyme disease p. 144

mechanism (diagram) p. 184

prophylaxis p. 194

Transcript

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Penicillins are antibiotics that got their name from the Penicillium mold, 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 - the inhibition of cell wall synthesis in bacteria.

So, our body consists of multiple eukaryotic cells, while bacterias are prokaryotic, meaning they are primitive, single cellular organisms.

Most have a slimy capsule made out of polysaccharides and a cell wall which encapsulates and protects the bacteria like a suit of armor and offers structural support.

Bacterial cell walls are made of a substance called peptidoglycan, or murein.

Peptidoglycan is a molecule composed out of long strands of amino polysaccharides running in parallel.

These are made of 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.

At the tips of the NAM subunits are tetrapeptide and pentapeptide chains, protruding from NAM subunits.

These peptide chains can link to other peptide chains from the neighboring strands through a process known as transpeptidation.

This is carried out by an enzyme called DD-transpeptidases, or penicillin binding proteins, or PBPs.

Now these enzymes are like locks and there are specific binding area for the pentapeptides keys to fit into.

Once the key goes in the lock, the PBP enzymes fuse them together, creating a stable link between the two amino polysaccharide strands and strengthen the cell wall.

In essence, all beta lactam antibiotics, like the penicillins, 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 gets 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!

Now, some bacteria have developed resistance to beta lactam antibiotics.

The most notable is the notorious staphylococcus aureus, which evolved an enzyme called beta lactamases or penicillinases that breaks down the beta lactam ring within the antibiotic, rendering it ineffective.

In response, we started adding beta lactamase inhibitors, such as clavulanic acid, that would bind to beta lactamases and inactivate them, like the gum into the keyhole.

Another approach was to create new kinds of beta lactam antibiotics like methicillin, which has a large side chain that wouldn’t “fit” into the keyhole of the beta lactamase.

They did work quite well, until some staphylococcus aureus developed PBP site mutations that changed the shape of the keyhole.

So even if beta lactamase enzymes can’t break down these antibiotics, they won’t fit into the PBP enzyme and thus won’t work.

We call these bacteria methicillin resistant staphylococcus aureus, or MRSA.

This poses a huge problem, as it makes MRSA virtually untreatable by beta lactam antibiotics.

To treat MRSA, we resort to so-called reserve antibiotics belonging to the glycopeptide antibiotics, like vancomycin and teicoplanin.

But, even that might come to an end, as MRSA is also developing vancomycin resistance, becoming VRSA.

Now going back to penicillins, we can divide these medication into three main groups based on their spectrum of activity - which is how many different species of bacteria can they effectively treat, and how vulnerable are they to beta lactamases.

Examples of narrow spectrum, susceptible to beta lactamase medication are penicillin G, applied IV and penicillin V, applied perorally.

These are the classics, still quite usable against common gram positive bacteria like streptococcus pyogenes that cause pharyngitis, and gram negative bacteria like neisseria meningitidis, that causes, well, bacterial meningitis.

They are also effective against spirochetes - such as treponema pallidum, that causes syphilis, or borrelia burgdorferi, that causes Lyme disease.

They, however, do not work well against a lot of Gram negative aerobes, and some of the bacteria they used to treat well back in the day, like Staphylococcus aureus, strains of streptococcus pneumoniae, and recently, neisseria gonorrhoeae, have developed resistance.

Now, we want to make a simple and fun mnemonic that’ll help you efficiently memorize and retain all these crazy pharm facts! So imagine a street that’s wide at one end and very narrow at the other. We will put our narrow spectrum drugs right in the middle of the street, which is kind of narrow.

This group of drugs will be represented by an artistic “penda” holding a giant pen which represents penicillin.

His drawing will represent the bugs that this class of medication treats, which includes a large pie at the bottom for streptococcus pyogenes.

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. "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)
  5. "Management of allergy to penicillins and other beta-lactams" Clinical & Experimental Allergy (2015)
  6. "Penicillins" Drugs (1993)
  7. "Antibiotic Resistance in Streptococcus pneumoniae" Clinical Infectious Diseases (1997)