Mechanism of Action of tetracyclines
In order to understand the mechanism of action of tetracyclines, and therefore their role as antibiotics, it is important to have a basic understanding of bacterial protein synthesis in bacteria. An outline of this process at the ribosomal level is given in the diagrams below:
Figure 1: Taken from Simmer (2003)
Figure 1 shows the importance of the binding of aminoacyl-tRNA at the A site to allow successful elongation of the peptide chain (shown in the first step of elongation in Figure 1). In bacteria, the tetracyclines inhibit protein synthesis at the level of the ribosome through a process of disruption of codon-anticodon interactions between tRNA and mRNA. As a result of this the binding of aminoacyl-tRNA to the ribosomal acceptor (A) site is prevented and bacterial growth is inhibited (Gale et al., 1981; Chopra, 1985). The precise mechanism by which the aminoacyl-tRNA is prevented from attaching to the A site by the tetracyclines is not understood. It has been suggested that inhibition is likely to result from interaction of these antibiotics with the 30S ribosomal subunit since many of the tetracyclines are known to bind strongly to a single site on the 30S subunit (Chopra 1985 cited Chopra et al., 1992)
Tetracyclines also bind to DNA, proteins and synthetic polynucleotides but it is only the binding to ribosomes that is inhibitory and, therefore, has a therapeutic effect (Gale et al., 1981).
The structure of the tetracycline drug molecules can affect their antibacterial activity. “Features important for antibacterial activity among the tetracyclines are maintenance of the linear fused tetracycle, naturally occurring (a) stereochemical configurations at the 4a, 12a (A-B ring junction), and 4 (dimethylamino group) positions, and conservation of the keto-enol system (positions 11, 12, and 12a) in proximity to the phenolic D ring” (Chopra and Roberts, 2001). Research carried out by McCormick et al. (1957 cited Gale et al., 1981) also draws attention to the fact that the configuration of the 4-dimethylamino group must not be reversed (which would give 4-epitetracycline) as this would cause antibacterial activity to be lost.
However, since the precise mechanism by which tetracylines work is not fully understood, further knowledge of how the structure of the drug molecules affects their function as antibiotics is not known.
Social impact of tetracyclines
The basic health of a population is essential for society. The US Food and Drug Administration, as well as the British National Formulary list a range of indications for administering tetracyclines. A target area concerning the use of tetracyclines is the current epidemic of sexually transmitted infections (STIs). One bacterium susceptible to tetracyclines includes Chlamydia trachomatis which is responsible for Chlamydia. If untreated, Chlamydia can lead to serious health complications including infertility and as the condition exhibits asymptomatic effects, rapid intervention is necessary.
National statistics state that Chlamydia is the most common STI in the UK and has been on the rise since the early 1990’s. Chlamydia can potentially affect any sexually active individual; however figures dictate that 15 to 24 year olds are at higher risk and the majority of cases are found in women. Chlamydia infections can possibly spread in pregnant women, passing the disease onto their children who may be born premature and with serious conditions such as blindness and pneumonia. The issue for society arises as tetracyclines, normally the primary choice for Chlamydia patients, have been shown to possess toxic effects on bones and therefore must not be distributed to children under the age of eight and pregnant women if impaired development of the foetus’s bone structure is possible.
An additional common use for tetracycline is in patients with acne. Tetracycline is often prescribed for patients with moderate to severe acne. The drug targets inflammatory lesions caused by Propionbacterium acnes affecting the pilosebaceous unit of the skin. The University of Newcastle-Upon-Tyne reported in the ‘Journal of Dermatological Treatment’ that there was a shift in the peak age incidence of acne between 14-26 year olds. Therefore acne is making an impact on the working population.
Although tetracyclines target bacterial diseases, a preventative approach to control the spread of disease would be ideal. However demographic changes, including a steep increase in populations and consequently urbanisation leads to overcrowding. The resulting situation can potentially lead to poor sanitisation and the spread of diseases including respiratory infections. In more economically developed countries this issue can be tackled as tetracyclines are dispensed for diseases including respiratory mycoplasma infections and exacerbations of chronic bronchitis caused by Hemophilus influenza. However on a global scale, lesser economically developed countries without funding or national health services, as in the UK, see an increased level of occurrence of diseases in lower and middle social classes.
Our final point concentrates on one of the drawbacks of tetracyclines. As tetracyclines are common broad spectrum antibiotics, their use has encouraged evolutionary transformation and subsequently the prevalence of bacterial resistant strains. Resistance of tetracyclines has been identified and so to a certain degree, limits their use. Future implications include the degree of effectiveness they directly impose on infections. There are many relative contributors when discussing the cause of resistance strains. For example many doctors have been criticised for prescribing antibiotics too freely to the extent that the European centre of Disease Prevention and Control sent out letters to every general practioner to reiterate to them the complications of routinely prescribing these drugs.
Many civic groups have been created to increase public awareness of the dangers of resistance strains of antibiotics including tetracyclines. The underlying fear is that antibiotics will eventually cease to be the effective tool in fighting infections, limiting choices for both physicians and patients. In November 2008, 27 European member nations celebrated ‘Antibiotic Awareness Day’. Their objectives included raising awareness on how to use antibiotics in a responsible way, hoping for them to remain effective for the future.