How Major Antibiotics Work and a Possible Benefit of Arylomycins
Antibiotics and Disease
Antibiotics are vital chemicals that destroy the bacteria that make us sick. The methods of action of five major categories of antibiotics are described below. The drugs in the categories are commonly prescribed to treat disease. Unfortunately, some of them are losing their effectiveness.
Antibiotic resistance in bacteria is a serious problem at the moment and is becoming worse. Some diseases are much harder to treat than they were in the past. Discoveries of new and potentially important antibiotics are always exciting. One group of chemicals that may provide us with effective drugs to fight bacteria is the arylomycins.
The choice of antibiotic depends on a variety of factors. One is whether the drug is a narrow-spectrum antibiotic (one that affects a narrow range of bacteria) or a broad-spectrum medication that is effective against a wide range of bacteria. Other factors that are considered are how effective the drugs are at treating a particular disease and their potential side effects.
Why Don't Antibiotics Harm Our Cells?
Our body is made of cells. Antibiotics are able to harm bacterial cells but not ours. The explanation for this observation is that there are some important differences between the cells of bacteria and those of humans. Antibiotics attack a feature that our cells don’t possess or that is slightly different in us.
The action of current antibiotics depends on one of the following differences between bacteria and humans. Bacterial cells are covered by cell walls, while ours aren't. The structure of the cell membrane in bacteria and humans is different. There are also differences in the structures or molecules used to make proteins or copy DNA.
Beta-lactam or β-lactam antibiotics are broad-spectrum medications. The group includes penicillin, ampicillin, and amoxicillin. Penicillin is a natural antibiotic made by a mold, which is a type of fungus. Most antibiotics were discovered in fungi or bacteria, which produce the chemicals to destroy the kinds of bacteria that can harm them. Ampicillin and amoxicillin are semi-synthetic drugs derived from penicillin. Cephalosporins and carbapenems are also beta-lactam antibiotics.
The benefit of beta-lactam antibiotics is related to the fact that bacteria have a cell wall around their cell or plasma membrane while our cells don’t. The wall is a relatively thick and strong layer that protects the bacterial cell. It's made of peptidoglycan. The cell membrane performs vital functions but is much thinner than the wall.
Peptidoglycan contains chains of alternating NAG (N-acetylglucosamine or N-acetyl glucosamine) and NAM (N-acetylmuramic acid) molecules, as shown in the illustration above. Short cross-links made of amino acids connect the chains and give strength to the wall. One of the steps in the formation of the cross-links is controlled by penicillin-binding proteins (PBPs). Beta-lactam antibiotics bind to PBPs and prevent them from doing their job. The cross-links are unable to form and the weakened cell wall breaks. The bacterium dies, often as a result of fluid entering the cell and causing it to burst.
Like many antibiotics, macrolides are natural chemicals that have given rise to semi-synthetic versions. Erythromycin is a common macrolide. It's made by a bacterium once named Streptomyces erythraeus. The bacterium is currently known as Saccharopolyspora erythraea.
Macrolides are effective against most gram-positive and some gram-negative bacteria. They inhibit protein synthesis in the bacteria, which kills the microbes. Proteins are a vital component of cell structure and function.
The process of protein synthesis can be summarized as follows.
- DNA contains chemical instructions for making proteins. The instructions are copied into messenger RNA or mRNA molecules, a process known as transcription.
- The mRNA goes to cell structures called ribosomes. The proteins are made on the surface of these structures.
- Transfer RNA or tRNA molecules bring amino acids to the ribosomes and "read" the instructions in the mRNA.
- The amino acids join in the correct order to make each of the required proteins. The process of building a protein molecule on the surface of a ribosome is known as translation.
Macrolides bind to the surface of bacterial ribsomes, stopping the process of protein synthesis. Ribosomes contain two subunits. In bacteria, these are known as the 50s subunit and the 30s subunit. The second subunit is smaller than the first one. (The s stands for Svedberg unit.) Macrolides bind to the 50s subunit.
Gram staining is a way to distinguish gram-positive cells from gram-negative ones. Gram-positive cells look purple after the staining procedure and gram-negative ones look pink. The different results reflect differences in structure. In general, a gram-positive cell has a single cell membrane surrounded by a cell wall. Gram-negative cells generally have a membrane both on the outer surface of their cell wall and on the inner surface.
Quinolones are found in various places in nature, but the ones used as medicines are generally synthetic. Most quinolones contain fluorine and are known as fluoroquinolones. Ciprofloxacin is a common example of a fluoroquinolone. Quinolone antibiotics are effective against both gram-positive and gram-negative bacteria.
A bacterial cell divides to make two cells in a process called binary fission. Before the division starts, the DNA molecule in the cell replicates, or makes a copy of itself. This enables each of the cells produced by fission to have an identical copy of the molecule.
A DNA molecule consists of two strands wound around each other to form a double helix. The helix unwinds in one section after another in order for replication to occur. DNA gyrase is a bacterial enzyme that helps to relieve strains in the DNA helix as it unwinds. The strains develop in areas that become "supercoiled" as the DNA helix unravels.
Quinolone antibiotics kill bacteria by inhibiting DNA gyrase. This stops DNA from replicating and prevents cell division. In some bacteria, quinolones inhibit an enzyme called topoisomerase IV instead of DNA. This enzyme also plays a role in relaxing DNA supercoils.
Possible Side Effects of Fluoroquinolone Use
Quinolones have been widely prescribed because they can be very helpful. Like all medications, they can cause side effects. These effects may be mild, but unfortunately some people experience major problems after using the drugs. Scientists are now paying attention to this situation and are investigating the effects of the medications.
There is enough evidence of potential harm from fluoroquinolones for the FDA (Food and Drug Administration) to issue a warning about the use of the antibiotics. The FDA is a United States government organization. The organization says that the drugs can cause "disabling side effects involving tendons, muscles, joints, nerves and the central nervous system. These side effects can occur hours to weeks after exposure to fluoroquinolones and may potentially be permanent". The document containing the warning is listed in the "References" section below.
Despite the FDA's warning, the organization says that in some serious illnesses the benefits of fluoroquinolones outweigh the risks. It also says that the drugs should still be used to treat certain conditions for which no other effective treatment is available.
Fluoroquinolones have risks and benefits that should be considered very carefully. It’s important that both health care providers and patients are aware of both the risks and benefits of fluoroquinolones and make an informed decision about their use.— Edward Cox, M.D., Food and Drug Administration
Tetracyclines and Aminoglycosides
The first tetracyclines were obtained from soil bacteria in the genus Streptomyces. As is the case with most antibiotics, semi-synthetic forms are now produced. Tetracycline is the name of a specific antibiotic in the tetracyclines category. It's sold under various brand names, including Sumycin. It's most notable side effect is that it can cause permanent staining of the teeth in young children.
Tetracyclines are broad-spectrum antibiotics characterized by four rings in their molecular structure. They kill gram-positive and gram-negative bacteria that are aerobic (ones that require oxygen in order to grow). They are much less successful at destroying anaerobic bacteria. Like macrolides, they join to the bacterial ribosome and inhibit protein synthesis. Unlike macrolides, they bind to the 30s subunit of the ribosomes.
Aminoglycosides are narrow-spectrum antibiotics. They affect aerobic, gram-negative bacteria and some anaerobic gram-positive bacteria in the class Bacilli. Streptomycin is an example of an aminoglycoside. It's produced by a bacterium named Streptomyces griseus. Like tetracyclines, aminoglycosides harm bacteria by binding to the 30s subunit of the ribosome and thereby inhibit protein synthesis.
Unfortunately, aminoglycosides sometimes cause harmful side effects. They can be toxic to the kidney and the inner ear. They cause sensorineural hearing loss and tinnitus in some patients.
The ability of a bacterium to survive in the presence of antibiotics is known as antibiotic resistance. Arylomycins could be useful in hindering antibiotic resistance because they attack bacteria in a different way from other current antibiotics.
Many antibiotics are not as helpful as they once were due to the development of antibiotic resistance. The process happens because bacteria obtain genes from other bacteria or experience changes in their own collection of genes over time.
Individual bacteria that have obtained or developed a helpful gene variant will survive when exposed to an antibiotic. They pass a copy of the beneficial variant to their offspring during reproduction. Individuals without the variant will be killed by the antibiotic. As this process repeats, the population will gradually become resistant to the drug.
Unfortunately, scientists expect bacteria to develop resistance to any antibiotic given enough time. We have the ability to slow this process down by using antibiotics only when necessary and by using them correctly when they are prescribed. This would give us more time to find new drugs. A new antibiotic group that might be helpful in the fight against bacteria is the arylomycins.
The white circles in the dishes above contain antibiotics. The clear areas represent regions where the bacterial culture has been killed by antibiotics. Bacteria that are able to grow around the white circles are resistant to the antibiotics.
Arylomycins fight gram-negative bacteria. Though there are exceptions, gram-negative bacteria are often more dangerous for us. The chemicals are of interest because they kill bacteria by a different method from other antibiotics that are used medicinally.
Most of our current antibiotics destroy bacteria by interfering with the cell wall, the cell membrane, or protein synthesis. A few affect the structure or function of DNA or interfere with folic acid synthesis. (Folic acid is a form of vitamin B.) Arylomycins work by a different mechanism. They inhibit a bacterial enzyme called bacterial type 1 signal peptidase. Since we haven't used arylomycins as antibiotics yet, many bacteria may still be susceptible to their effects.
In their natural form, arylomycins kill a narrow range of gram-negative bacteria and aren't very powerful. Researchers have recently created an artificial version known as G0775, which seems to be both more effective and to have a broader spectrum of activity. The discovery is exciting. No new antibiotic for gram-negative bacteria has been approved in over fifty years in the United States.
Although the illustrations in this article show rod-shaped bacteria, the organisms may also be spiral-shaped or spherical.
Signal peptidases are membrane enzymes. They remove the signal peptide extension from proteins that move through the cell membrane to the surface of the bacterium. The removal of the extension is important because it activates the proteins, allowing them to do their job. The signal peptide attached to a protein acts as a marker "telling" the enzyme that the protein needs to be activated. If signal peptidases are inhibited, the proteins aren't activated and can't carry out their functions, which are essential for the life of the cell. As a result, the cell dies.
In gram-positive cells, the signal peptidase enzyme is located near the surface of the cell membrane. In gram-negative cells it's located near the surface of the inner membrane. Drugs designed to attack gram-negative cells have to travel through the outer membrane and the peptidoglycan layer (or the cell wall) in order to reach the inner membrane. This is one reason why it's often hard to create effective antibiotics for the cells. G0775 is able to penetrate the outer layers of the cell and reach the signal peptidase, however.
Potential Benefits and Problems
One problem with G0775 is that the drug has been tested in isolated cells and mice but not in humans. The good news is that it has destroyed a range of bacteria, including gram-negative, gram-positive, and multidrug resistant bacteria.
The actions of arylomycins aren't as well understood as those of many other antibiotics. Another problem is that a concern about toxicity needs to be investigated. The arylomycin molecule has some structural features that remind certain researchers of molecules that are toxic to the kidneys. They need to find out whether the similarity is unimportant or something to worry about.
Some additional candidates for new antibiotics have been found. It takes time to prove that a drug is both helpful and safe for humans. Hopefully new candidates will continue to appear and tests will show that both optimized arylomycin and other potentially helpful chemicals are safe for us.
Information about antibiotics from the University of Utah
Antibacterial drugs from the Merck Manual
FDA warning for fluoroquinolone antibiotic use
Antibiotic quells resistance from the Royal Society of Chemistry
A new antibiotic from Science (An American Association for the Advancement of Science publication)
© 2018 Linda Crampton