If you were a cell, you wouldn't get very far in life without synthesizing the nucleic acids DNA and RNA. In this lesson, learn how rifamycins and quinolones kill bacteria by inhibiting these important processes.
Inhibition of Nucleic Acid Synthesis
In a bacterial cell, or any kind of cell for that matter, the nucleic acids DNA and RNA are incredibly important molecules. When a cell divides, it must first replicate its DNA to give the new cell what basically amounts to its instruction manual for life. And in the daily life of a cell, transcription of DNA into RNA is a major step in the assembly line that creates proteins. It's easy to see that if DNA or RNA synthesis are inhibited, a cell won't be able to get anything done at all!
So, inhibiting nucleic acid synthesis sounds like a great strategy for an antibiotic. And luckily for us, the enzymes that carry out DNA and RNA synthesis are different enough between eukaryotic and prokaryotic cells that selective toxicity can be achieved. In this lesson, we'll learn about two major classes of antibiotics that inhibit nucleic acid synthesis: rifamycins and quinolones. We'll see how these antibiotics work, why they're selectively toxic, and how bacteria can become resistant to them.
The rifamycins are a family of antibiotics that inhibit bacterial RNA polymerase. Rifamycins work by binding to the bacterial DNA-dependent RNA polymerase, the enzyme that is responsible for transcription of DNA into RNA. The antibiotic molecule is thought to bind to the polymerase in such a way that it creates a wall that prevents the chain of RNA from elongating. Rifamycins are bactericidal antibiotics. In the presence of rifamycins, bacteria can't transcribe any genes that they need to carry out their normal functions, so they die.
Rifamycins are broad-spectrum antibiotics, meaning they're effective against many types of bacteria, including Gram-negative, Gram-positive, and obligate intracellular bacteria. There are two main reasons for this. First, the rifamycin molecule can penetrate well into cells and tissues. This means that, unlike some antibiotics that can't cross certain types of bacterial cell walls, the rifamycins can almost always get in and gain access to their target enzyme. And second, the bacterial RNA polymerase is well-conserved even among very different bacteria. This means that the enzyme's structure is similar enough that the rifamycins can bind well to their target in diverse types of bacteria.
And how do the rifamycins achieve selective toxicity? After all, our cells need RNA polymerases too! Luckily for us, rifamycins do not bind to eukaryotic RNA polymerases, so our own cells can continue to transcribe genes normally even when we are taking these antibiotics.
The best-known and most effective member of the rifamycin family is rifampin, which is also known as rifampicin. A major use of rifampin is in the treatment of mycobacterial diseases, such as tuberculosis and leprosy. Since mycobacteria are obligate intracellular bacteria, they live within host cells, where they're protected against many antibiotics that can't get inside. Rifamycins can penetrate well into cells and tissues, so they're a good first choice for mycobacterial infections. However, as with any antibiotic, there are bacteria that are resistant to the rifamycins. The most common way for bacteria to become resistant to rifamycins is to acquire mutations that alter the structure of the RNA polymerase in such a way that rifamycins can't bind to it as well.
Quinolones and Fluoroquinolones
The second major class of antibiotics that inhibit nucleic acid synthesis is the quinolones and their derivatives, the fluoroquinolones. These are synthetic antibiotics that were first developed in the 1960s. Drugs in this family, such as nalidixic acid, ciprofloxacin, and norfloxacin, work by inhibiting enzymes that are required for bacterial DNA synthesis. So, in contrast to the rifamycins, which inhibit transcription of DNA into RNA, the quinolones and fluoroquinolones inhibit DNA replication. But fortunately for us, they don't bind to eukaryotic enzymes for DNA replication, so they're selectively toxic.
The major target of quinolones and fluoroquinolones, especially in Gram-negative bacteria, is the enzyme DNA gyrase, which is also known as topoisomerase II. This enzyme normally relieves torsional stress during DNA replication. What does that mean? Well, as the replication fork moves along the bacterial chromosome, the strand of DNA in front of it becomes supercoiled, or excessively twisted. DNA gyrase binds to the DNA, cuts one of the strands, and allows it to untwist a bit before resealing the strand. But when quinolones or fluoroquinolones are present, DNA gyrase is inhibited and cannot reseal the DNA strands. This causes the bacterial chromosome to break into small fragments, and this extensive DNA damage kills the bacterium.
In Gram-positive bacteria, the major target of quinolones and fluoroquinolones is a related enzyme called topoisomerase IV. This enzyme normally cuts the interlinked daughter chromosomes apart from each other after DNA replication is finished. When topoisomerase IV is inhibited by these antibiotics, the same result occurs: the bacterium dies because of DNA breakage. All this talk about bacterial death lets us know that quinolones and fluoroquinolones are bactericidal antibiotics. And what about their spectrum of activity? Quinolones, such as nalidixic acid, have a fairly narrow spectrum of activity and work best against Gram-negative bacteria. They're most commonly used to treat bladder infections.
Fluoroquinolones, on the other hand, work against Gram-negative bacteria and some Gram-positive bacteria as well, meaning they have a relatively broad spectrum of antibacterial activity. The fluoroquinolone ciprofloxacin became famous in the early 2000s when it was used to treat anthrax infections, which are caused by the Gram-positive bacterium Bacillus anthracis. Ciprofloxacin can be used to treat many other kinds of infections as well.
As you may suspect, even though quinolones and fluoroquinolones work really well, bacteria can become resistant to them. The main way this can happen is if the bacteria acquire mutations that change the structure of the antibiotics' target enzymes, DNA gyrase and topoisomerase IV.
Today, we've seen how antibiotics can shut down some of the most important functions of bacterial cells, synthesis of the nucleic acids DNA and RNA. We learned about two major classes of antibiotics, the rifamycins and the quinolones and fluoroquinolones.
Rifamycins inhibit the bacterial RNA polymerase, preventing transcription, and they are special because they can penetrate well into cells and tissues. The best-known rifamycin antibiotic is rifampin, and one of its main uses is in the treatment of mycobacterial infections, such as tuberculosis and leprosy. This drug is a good choice because mycobacteria live inside host cells and are thus hard to reach with many antibiotics.
Quinolones and fluoroquinolones inhibit DNA replication by targeting the bacterial enzymes DNA gyrase, aka topoisomerase II, and topoisomerase IV. DNA gyrase untwists the DNA during replication to relieve torsional stress, and topoisomerase IV cuts the daughter chromosomes apart after replication. When these important enzymes are inhibited by antibiotics, DNA breakage occurs and the bacteria die because of the extensive DNA damage. The quinolone nalidixic acid is often used to treat bladder infections, and the fluoroquinolone ciprofloxacin is used to treat many infections, including anthrax.
Once you've finished with this lesson, you will have the ability to:
- Describe how rifamycins function and their unique characteristic
- Provide an example of a rifamycin antibiotic and identify the diseases it treats
- Explain how quinolones and fluoroquinolones function
- Identify an example of a quinoline and a fluoroquinolone antibiotic and which infection each treats