DNA/RNA SYNTHESIS

DNA/RNA synthesis

The synthesis of nucleic acids (DNA and RNA) are vital to the functionality of any living cell. These processes allow the cell to replicate and pass on genes, as well as protein synthesis. Antibiotics that inhibit the production of nucleic acids are known as nucleic acid inhibitors, with the two major groups: DNA and RNA inhibitors.

                      

Enzymes involved in DNA and RNA synthesis differ between the prokaryotic and eukaryotic cells, therefore selective toxicity can be achieved.

 

Example of RNA synthesis inhibitors

 

Rifamycins

 

Rifamycins bind to the RNA polymerase, which is vital to transcribing DNA into RNA. When this antibiotic binds to the polymerase, it prevents the RNA chain from elongating, resulting in the non-synthesis of proteins essential to the cell's survival (see Figure 1).  Because rifamycins can penetrate cells and tissues, they are broad spectrum antibiotics.

 

Antibiotic resistance can develop through the mutation of RNA polymerase, altering it’s structure. This changes the structure of RNA polymerase, and rifamycins can’t bind to it as well.

 

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Figure 1. Inhibition of RNA polymerase by rifamycins, resulting in non-synthesis of essential proteins and cell death.

Example of DNA synthesis inhibitors

 

Quinolones and fluoroquinolones are also selectively toxic in that they don’t bind to eukaryotic cells.

 

In gram-negative bacteria, their target is DNA gyrase (Topoisomerase II) which relieves torsional stress during DNA replication. As the replication fork moves down the DNA strand, the DNA becomes supercoiled. DNA gyrase relieves this tension by cutting the DNA, allowing it to uncoil, and resealing it again. In the presence of quinolones and fluoroquinolones, DNA gyrase is inhibited, preventing it from resealing the DNA strand. This results in the DNA being cut into small fragments and eventually cell death (see Figure 2).

 

In gram-positive bacteria, their target is Topoisomerase IV. This enzyme cuts the daughter cells after replication. In the presence of quinolones and fluoroquinolones, Topoisomerase IV is inhibited, resulting in DNA breakage and eventually cell death.

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Figure 2. Inhibition of DNA gyrase by quinolones and fluoroquinolones, resulting in DNA fragments and cell death.