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Protein synthesis inhibitors: Aminoglycosides

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Protein synthesis inhibitors: Aminoglycosides

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Protein synthesis inhibitors: Aminoglycosides

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Aminoglycosides are antimicrobial antibiotics that inhibit bacterial ribosomes, which are the organelles that make proteins.

Genes are used to synthesize proteins in 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.

Translation is also known as protein synthesis, and it’s when ribosomes use mRNA to assemble proteins 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.

In both eukaryotic and prokaryotic cells, 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 known as 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.

Transport RNA, or tRNA, carrying different amino acids can bind to these codons with their matching anticodons.

The complete ribosome-mRNA complex 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 in the ribosome, which unlocks the A site for the next tRNA.

A process called proofreading occurs here where only tRNAs with the matching anticodon can bind to corresponding mRNA codon.

After the next tRNA binds at the A site, the amino acid detaches from the tRNA in the P site, and gets attached to the amino acid in the A site by the enzyme peptidyl transferase.

This step is called transpeptidation because the peptide chain is transferred from the P site tRNA to the A site tRNA.

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, called translocation, the ribosome slides across the mRNA, and the A site sits above a new codon, the tRNA that was in the A site slides over to the P site, and the tRNA in the P site slides over to the E site.

Now, a new tRNA can bind at the A site, and the process repeats until a long peptide chain, called a protein, is synthesized.

Finally, termination happens when the ribosome comes across a termination codon on the mRNA. tRNA can’t bind to these, so it signals the end of protein synthesis.

To start working, aminoglycosides need to enter the bacteria, and frankly, they aren’t very good at it.

Gram positive bacteria have a thicker cell wall compared to Gram negative bacteria, so aminoglycosides can’t even penetrate them.

They also require an O2-dependent cotransporter on the cell membrane to be transported into the cell.

Obviously, these aren’t seen in strictly anaerobic bacteria, so we can rule out aminoglycosides as a treatment for anaerobic infections.

So on their own, aminoglycosides can only target Gram negative aerobic bacteria.

Once they enter the bacteria, their main mechanism of action is to irreversibly bind to the 30S subunits and prevent the formation of the ribosome-mRNA complex, thus inhibiting the initiation of protein synthesis and reducing the amount of proteins being synthesized.

They can also interfere with the proofreading process, thus causing errors in the protein’s amino acid sequence.

These faulty proteins will eventually lead to the death of the bacteria.

Finally, a 30s subunit bound to an aminoglycoside can get stuck to the mRNA.

This prevents translocation where the ribosome slides over to the next codon.

Depending on the concentration applied, aminoglycosides can work as bacteriostatic, which stops the bacteria from multiplying, or bactericidal, which outright kills them.

Aminoglycosides are also known for their strong post antibiotic effect because they remain effective hours after their levels have dropped below the minimum inhibitory concentration, or MIC, which is the minimum concentration that inhibits the growth of a microorganism.

Examples of the aminoglycoside family include amikacin, gentamicin, neomycin, streptomycin, and tobramycin.

They are used to treat a wide variety of infections in the respiratory tract, urinary tract, blood, bone, and soft tissues.

It is used mainly against aerobic Gram negative bacteria like Proteus species, Escherichia coli, Klebsiella pneumoniae, Enterobacter species, and Serratia species.

Streptomycin is often used against mycobacterium tuberculosis, which thrives in the oxygen-rich lung tissue.

Tobramycin is given topically to treat eye infections, or in a nebulized form to treat Pseudomonas aeruginosa infections in people with cystic fibrosis.

Now, remember how the thick cell wall on Gram positive bacteria stops aminoglycosides?

Sources
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  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)
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  6. "Versatility of Aminoglycosides and Prospects for Their Future" Clinical Microbiology Reviews (2003)
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