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Tetracycline resistance

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Related terms
Background
Methods
Research
Implications
Limitations
Safety
Future research
Author information
Bibliography

Related Terms
  • Antibiotic pressure, antibiotic resistance, antibiotics, doxycycline, mutation, resistance to tetracycline, ribosome protection, tetA, tetB, tetC, tetM, tetracycline-resistant determinants, tetracycline, tetracycline efflux, tetracycline modification.

Background
  • Tetracyclines are a group of antibiotics with activity against a wide variety of gram-positive and gram-negative bacteria. A gram stain is a type of test that helps differentiate bacteria. In a gram stain, the gram-positive bacteria stain dark blue, while the gram-negative do not retain the stain and have a red or pink color.
  • Because of their wide range of action, tetracyclines are called broad-spectrum antibiotics. Tetracyclines slow down a bacterium's ability to make protein. As a result, the bacterium cannot replicate, meaning it cannot produce new bacteria. Because they inhibit the growth and reproduction of an organism's activity without killing it, they are known as bacteriostatic agents. In contrast, bactericidal agents are antibiotics that kill the bacteria.
  • In addition to their action against gram-positive and gram-negative bacteria, tetracyclines exhibit activity against many other organisms, including anthrax, chlamydia, mycoplasmas, rickettsiae, and protozoan parasites. Tetracycline is also useful in the treatment of drug-resistant P. falciparum malaria. Because of its slow action, it is used in combination with a faster-acting drug, such as the antimalarial drug quinine.
  • Tetracycline became commercially available in 1953. The semi-synthetic, second-generation antibiotic doxycycline became available in 1967. A semi-synthetic antibiotic is a substance produced in a laboratory using natural products. A number of other naturally occurring and semi-synthetic types of tetracycline are also available. Each varies somewhat in the organisms it is effective against and in how long a dose remains effective.
  • Because of their favorable antimicrobial properties and their low incidence of serious side effects, tetracyclines are commonly used to treat infections in humans and animals. Several years after tetracycline was discovered, it was fed to livestock with the goal of reducing infections. Because it was found to not only reduce infections in livestock but also to have a profound effect on growth, tetracyclines are now also used as growth promoters for livestock.
  • The widespread use of tetracyclines has led to the unintended consequence of antibiotic resistance. Tetracycline resistance is on the rise and has limited the usefulness of this antibiotic.
  • In view of increasing bacterial resistance to tetracycline, researchers are attempting to establish the molecular basis of this resistance. The molecular basis of resistance is at the genetic level. Resistance is thought to develop through a genetic mutation, which limits or cancels the effect of an antibiotic. In addition, when a bacterium develops resistance to an antibiotic, it can transfer that resistance to other bacteria by releasing DNA that contains the resistance gene into the environment, where it is picked up by neighboring bacteria.

Methods
  • Antibiotic resistance appears to occur through spontaneous mutations that reduce an organism's sensitivity to a given drug or to an entire class of antibiotics. A single mutation may impart resistance to an antibiotic, but multiple mutations appear to be required for resistance to other drugs. Antibiotic resistance ranges from none to high. To treat life-threatening infections, a combination of antibiotics is often used, which may reduce the chance of the infection worsening because of antibiotic resistance.
  • Tetracycline slows bacterial growth by inhibiting protein synthesis. If a bacterium is unable to make protein, it cannot multiply. Antibiotic resistance occurs when the bacterium develops the ability to counteract the inhibition of protein synthesis. To date, three specific mechanisms of tetracycline resistance have been identified. These include ribosome protection, tetracycline efflux, and tetracycline modification. Tetracycline modification is less common than the other two.
  • Ribosome protection: Ribosome protection is made possible by a soluble protein that protects the bacterium from the harmful effects of an antibiotic. This protein shares a common ancestry with the GTPases, which are enzymes that can bind to and break up guanosine 5'-triphosphate (GTP). GTPases participate in protein synthesis and restore the bacterium's ability to replicate, or multiply.
  • Tetracycline efflux: Tetracycline efflux is the secretion of a protein by a bacterium. This protein attaches to the antibiotic and is expelled from the cell along with the antibiotic.
  • Tetracycline modification: Tetracycline modification requires a cytoplasmic protein, a protein found in cellular material that chemically changes tetracycline. This reaction can occur only in the presence of oxygen and nicotinamide adenine dinucleotide phosphate (NADPH). NADPH is a small molecule that is able to carry chemicals between enzymes. Tetracycline modification occurs only in vitro, that is, in a laboratory setting, not in a living organism.

Research
  • Many studies are focused on identifying tetracycline-resistant strains of various organisms in an attempt to understand the underlying mechanisms of their resistance. Furthermore, identification of the sites of resistant organisms (e.g., E. coli in uncooked foods) can reduce the risk of exposure to infection.
  • A number of studies are focused on identifying specific genes that provide resistance. By identifying these genes, researchers can analyze how they become resistant. Researchers can also develop methods for inactivating these genes and restoring the effectiveness of an antibiotic.
  • Ongoing research is being conducted by pharmaceutical companies to develop new antibiotics and new forms of existing antibiotics. Doxycycline is an example of a new antibiotic that was developed after the introduction of tetracycline. Doxycycline has a longer duration of action than tetracycline, which has the advantage of less frequent doses. When doxycycline was first introduced, it was effective against organisms that were resistant to tetracycline. However, bacterial resistance has also occurred with this drug.
  • Molecular biology research is being conducted on tetracycline-resistant determinants (something that contributes to the development of resistance). Current tetracycline resistance determinants under investigation include the tetA¸ tetB, and tetC genes. These genes are involved in tetracycline efflux, or the "pumping out" of tetracycline from the bacterium. The tetracycline resistance gene, tetM, which is found in both-gram positive and gram-negative bacteria, is also under investigation.

Implications
  • Overuse of antibiotics is a major contributor to bacterial resistance. Antibiotic overuse is called "antibiotic pressure," which increases the chances of a bacterium becoming resistant to an antibiotic. Bacteria that are sensitive to the antibiotic are destroyed, while those that are resistant flourish.
  • Antibiotic pressure may be exerted directly by using the antibiotic on a resistant strain of bacteria, thus favoring the growth of the very microorganism one is trying to eliminate. In addition, antibiotic pressure may occur indirectly, for example, through the inappropriate use of an antibiotic, which increases the opportunity for the bacterium to develop resistance. Examples of inappropriate uses include administering antibiotics to patients with a viral upper respiratory infection, adding antibiotics to animal feed to promote growth, taking an antibiotic that is not of sufficient strength, or not taking a prescribed antibiotic for the full amount of time.
  • A number of studies have found that patients often do not complete a full course of antibiotic treatment. This promotes the development of antibiotic resistance in some bacteria because the remaining bacteria have the opportunity to develop resistance. Conversely, an excessively long course of antibiotic treatment can also cause antibiotic pressure and favor the development of resistant strains.
  • To effectively reduce the incidence of antibiotic resistance, it is necessary to reduce the antibiotic pressure in the bacterial environment, such as the intestinal tract, environmental water, and animal reservoirs.

Limitations
  • Despite the development of new antibiotics, bacteria will continue to evolve and develop resistance.

Safety




Future research
  • Future research will focus on the development of new antibiotics and the investigation of the genetic mechanisms involved in resistance.
  • Research on antibiotic resistance will focus on the three known mechanisms of resistance: ribosome protection, tetracycline efflux, and tetracycline modification. Perhaps other mechanisms of resistance will be discovered as research progresses.

Author information
  • This information has been edited and peer-reviewed by contributors to the Natural Standard Research Collaboration (www.naturalstandard.com).

Bibliography
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The information in this monograph is intended for informational purposes only, and is meant to help users better understand health concerns. Information is based on review of scientific research data, historical practice patterns, and clinical experience. This information should not be interpreted as specific medical advice. Users should consult with a qualified healthcare provider for specific questions regarding therapies, diagnosis and/or health conditions, prior to making therapeutic decisions.

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