Tetracycline Essay: Mechanism, Treatments, Side Effects For Dizziness And Vertigo.

Current Treatments

Discuss about the Tetracycline for Dizziness and Vertigo.

Bacterial infections are caused when a harmful strain of bacteria enter the body. Less than 1% of the bacteria cause infections inside the body. These pathogenic bacteria are the main cause of symptoms and disease in humans. It causes infections like typhoid, tetanus, food borne diseases, cholera, tuberculosis and leprosy. The bacteria invade the bodies of the human beings and can survive and multiply. The body fluids as plasma is rich in vitamins, sugar and minerals that act as nutrients for the bacteria’s survival. Bacteria circumvent the immune system of the humans through many strategies. There is molecular mimicry, suppression of the antibiotics or release the antigen directly into the bloodstream. They also adopt strategies that are directed against the phagocytes that are microphages. The suppression of the antibiotics is the best form of attack by the bacteria where they suppress the specific cells that target and react against them. This mechanism is the main targeting site where the antibiotics work to stop the progression of disease or the pathogenic condition (Nguyen et al., 2014).

Out of all antibiotics, tetracycline is a broad spectrum antibiotic that is used extensively to treat bacterial infections. It is prescribed as it prevents the growth and spread of the bacterial infection. It is naphthacene antibiotic that inhibits the binding of aminoacyl-tRNA to the mRNA-ribosome complex. This results in the inhibition of protein synthesis. It binds to the 30s ribosomal subunit in the complex of mRNA translation machinery and is called 30s inhibitor.

It is 6-carbon ring fused together. It is bacteriostatic in nature; however, it has wide bacterial resistance. It slows down or stops the growth of the cells as it disrupts the processes that lead to synthesis of new proteins. They preferentially bind to the ribosome of the bacteria as there are structural differences in the RNA subunits. The transport system of the bacteria is exploited by tetracycline and that increases the concentration of the antibiotic within the host cell to be higher than the surrounding concentration. In this way, tetracycline works to target the bacteria and stops the progression of the bacterial infection.

The drugs within the tetracycline class are tetracycline, chlortetracycline, doxycycline, oxytetracycline and minocycline. However, among all these, doxycycline and minocycline antibiotics are the currently prescribed drugs under tetracycline classification. These kinds of tetracyclines have longer half time and better absorbed from the gastrointestinal tract. It requires only once-daily administration as the half time is about 17 hours.  The adverse events are also of low frequency and less side effects of these drugs. Doxycycline is excreted through intestinal tract and that allows treatment even in the renal insufficiency.

Tetracycline Mechanism of Action

The greatest advantage of tetracycline is that they are well absorbed from the gastrointestinal tract. They have a penetration power into the cells and various tissues. Tetracyclines are a broad class of antibiotics effective on gram negative and positive bacteria. The main mechanism of action lies in the inhibition of protein synthesis via binding to the bacterial ribosome 30s. Tetracycline is an effective prescribed anti-malarial drug and effective over many pathogens. It exerts its antibiotic effect by bacterial ribosome binding and as a result, the protein synthesis is arrested. Generally, bacterial ribosomes have a high-binding affinity for the 30s subunit ribosomes and allosteric action of tetracycline when bind to the amino acyl-tRNA at the acceptor site (A-site), protein synthesis is ceased (Forsberg et al., 2015).

Minocycline has the ability to cross the cell membranes being a potent anti-apoptotic agent. The mechanism of action lies in targeting the apoptotic signaling pathways. It is a synthetic derivative that is highly active against the resistant bacterial strains like Escherichia coli. According to a study conducted by Vedatam and Moller (2015) showed that this class of tetracycline is highly effective against the 87% of this strain of bacteria. The mechanism of action lies in the cessation of protein synthesis by binding to 30s ribosomal subunit that prevents the binding of tRNA to the mRNA-ribosome complex and interfere with the protein synthesis. Minocycline has less photosensitisation reaction as compared to other tetracyclines like doxycycline. It has a long half-life of 11 to 23 hours. It has high concentration in the tissues as it is widely distributed in the sputum and cerebrospinal fluid as compared to any other tetracyclines. As compared to blood, its concentration is higher in the body tissues with a percentage of 2 to 4 times higher. This drug has excellent administration in renal impaired patients. Generally, tetracyclines are greatly avoided in the impaired kidney patients, however, minocycline can be used in patients with kidney malfunctioning as the drug is eliminated through gastrointestinal and hepatobiliary tracts.  It has low level of bacterial resistance as compared to tetracycline. One of the common resistance mechanisms by the bacteria is that it produces a thick lipid bilayer that does not allow the antibiotic to penetrate. However, minocycline is the most lipid soluble among all the tetracyclines and so it has minimal antibiotic resistance.

The biggest disadvantage of minocycline is that it is most expensive than any other tetracyclines. It is highly contradicted in children leading to permanent teeth discoloration and enamel hypoplasia. The long-term consumption of this drug can give rise to complications like lupus-like syndromes leading to autoimmune responses where the body attacks its own cells. There are many symptoms of serum sickness-like reactions (SSLR) also occur where there is delayed allergic reaction and the body’s immune system interprets the drug as a foreign material. There is also intracranial hypertension or pseudotumor cerebri developed as a rare condition due to minocylcine use. Some vestibular side effects are also witnessed in minocycline and not in any other tetracyclines. It can cause nausea, severe dizziness, vomiting, ataxia and vertigo. According to a study conducted by Chang, A.K. and Olshaker (2014) vertigo was seen in 86% of the individuals. Hyper pigmentation is also manifested as a potential irreversible reaction. The hyper pigmentation of the skin increases with the duration of use, however, it is dose independent in nature. The daily administration of large amounts of ascorbic acid can help to prevent the hyper pigmentation.

Minocycline and Doxycycline as Current Treatments

Doxycycline are tetracyclines that are absorbed readily and bind to the plasma proteins at varying concentrations. They are concentrated in the bile by the liver and in the excretion in the urine and faeces in a biologically active form at high concentrations. It works by inhibiting the matrix metalloproteinases that contribute to activities of tissue destruction. After the oral administration, they are virtually readily absorbed. The half-life of this drug does not change in people with renal function impairment. It has the ability to inhibit the protein synthesis of the bacteria by binding to the 30s ribosomal subunit. It has a bacteriostatic activity against the gram negative and gram-positive bacteria. The greatest advantage of this drug is that it has excellent safety with least adverse effects (Stone et al., 2016). It is highly suitable for the impaired renal function patients as it is eliminated via non-renal modes with no accumulation. The half-life is also long with once or twice daily dosing. It is highly effective against all kind of common pathogens that are likely to cause infections in upper respiratory tract like Streptococcus pneumonia. It has great anti-inflammatory effects and against the penicillin-resistant pathogens. It is also effective in inhibiting the metalloproteinases that are enzymes inhibit the gelatine and collagen production. Most importantly, this drug does not affect the intestinal flora as it is completely absorbed in the body.

However, there are some disadvantages of Doxycycline. According to a study conducted by Dubey et al., (2015) showed that photosensitivity reaction manifested as an adverse effect of this drug. There is also a risk for intracranial hypertension and oesophageal ulceration. Moreover, prolonged use can result in superinfection.

There are a series of compounds that are developed to inhibit the 30s ribosomal subunit that is targeted by tetracycline. Neomycin and paromomycin are the aminoglycosides that were examined in bacterial cells Escherichia coli that have an inhibitory effect on the 30s ribosomal subunit. These drugs inhibit the protein synthesis, viable cell number and growth rate of the bacteria with inhibitory concentration of 50%. Paromomycin stimulate mistranslation via locking of the 30s particle so that mismatching of the base pair is stimulated in the presence of these antibiotics. This mechanism greatly suggest that these drugs affect the 30s ribosomal particle function having an inhibitory activity on the growing bacterial cells.

The mode of action of these aminoglycosides is to inhibit the protein synthesis via pleiotrpic actions leading to alteration in translation at the steps of initiation, elongation and termination. The naturally occurring crystal structure of the antibiotics and the semi-synthetic structures bound to the ribosomal particles have an insight into the facilitation and designing of the drugs targeting bacteria. These drugs causes misreading on the 30s subunit and paromomycin stimulate mistranslation by locking to 30s particle conformation so that the base pairs mismatch as stimulated by these antibiotics. Neomycin also works in a similar fashion locking the conformation that prevents the 30s subunit conformation and in turn prevents the synthesis and maturation of the 50s ribosomal subunit. In some bacterial cells, the accumulation and turnover of 30s stalled precursor particle that is combined with the inhibition of translation account for the antibiotic bacteriocidal activity (Zimmermann et al., 2016).

Side Effects of Tetracycline

Examples of naturally occurring tetracycline drugs are chlortetracycline, tetracycline and oxytetracycline. The semi-synthetic drugs are minocycline, methacycline and meclocycline. Based on the duration of action, tetracycline and chlortetracycline have half life of 6 to 8 hours. The drugs with immediate acting with half life of 12 hours like in metacycline and demeclocycline. The long acting drugs are 16 hours or more like doxycycline and minocycline.

Tetracycline is used for the treatment of various diseases including the gram negative bacterial infections. In pneumonia, tetracycline travels through the membranes via the porin channels and gets accumulated in the periplasmic space. The movement through the cytoplasmic membrane is driven by the energy of proton motive force. After tetracycline enters the bacterial cell, it bind reversibly to the 30s ribosomal subunit of the prokaryote that stops the protein synthesis.

A novel synthetic protocol for the synthesis of tetracycline analogs involves the synthesis of tetracycline ring system where a highly functionalised chiral enone (5) acts as the key intermediate using a convergent synthesis. This approach is useful for the preparation of hexacylcines, pentacylcines, C5-substituted or unsubstituted tetracyclines, 6-hydroxytetracyclines and tetracyclines with heterocyclic D-rings. The first step is the reaction of the enone with the anion that is formed by the deprotonation of the toluene (6) or benzylic halide undergoing metallation. This toluene deprotonation is useful in the preparation of 6-deoxytetracyclines that are without or with C5 substituent as well as for the pentacyclines. For this protocol, any kind of organometallic reagent can also be added during the cyclization process.

The structure activity relationships (SAR) of tetracyclines are synthesized to create new antibiotics that can overcome the resistance mechanisms of tetracycline mechanisms. It is the relationship between the chemical structure and its biological activity of the molecule. The SAR analysis helps to determine the chemical group that is responsible for evoking the target biological effect in the body (Marczak, Grabowski and Feder 2015). An active tetracycline has antibacterial activity that have a DCBA naphthacene ring that is linearly arranged with an A-ring C1-C3 diketo substructure. It also have an exocyclic C2 amide or carbonyl group. They act as protein synthesis inhibitors in the bacteria that need the amino group at teh C4 position and keto-enolic tautomers at the C1 and C3 positions of the A ring. The amino group that is present at the C4 position plays an important role in the antibacterial mechanism. The dimethylamino group at the C4 position with natural 4S isomer is pivotal for the optimization of antibacterial activities. The epimerization that occurs at the 4R isomer greatly decreases the activity of the Gram-negative bacteria. The chemical modification of the amide group at the C5 and C9 position greatly affects the bioactivity and are designed to generate antibacterial activities at varying degrees. In the tetracycline structure, the D ring is subjected to maximum change as it is highly flexible. The modifications done at the groups R1, R2 and R3 allows high bacterial specificity and in fulfilling the demands of the changing pharmacokinetics. This varying and flexible structure of tetracycline makes them effective antibiotics against bacterial infections.

Disadvantages of Minocycline

Extensive research is going on identifying the tetracycline-resistant strains of bacteria to understand the underlying mechanism that leads to resistance. Moreover, there is also ongoing research to study and identify the sites of the resistant pathogens so that the risk of exposure can be reduced in the bacterial infection. There is also research going on in identifying the specific genes that are responsible for the resistance. By identifying the resistant genes, it would be easy to develop methods that inactivate these genes. There is ongoing research to study the tetracycline-resistant determinants like tetA, tetB and tetC genes. These genes are responsible for pumping out of tetracycline from the bacterium called tetracycline efflux. The gene tetM, tetracycline resistant gene is under investigation that is found in gram negative and positive bacteria (Daghrir and Drogui 2013).

Although extensive research has been made to enhance the antibacterial activity of the tetracycline drugs, there is limited research made to reduce the anti-bacterial resistance. Despite of the new developments that are being made to study the bacterial resistance leading to development of new antibiotics, bacteria are continuing to evolve and develop resistance. Future research is required that would help to study the bacterial resistance and would be beneficial to develop new antibiotics. The investigations into the genetic mechanisms are required so that the underlying resistance mechanisms can be understood. As research progresses, study of antibiotic resistance should focus on the mechanisms of tetracycline efflux, ribosome protection and modification of tetracycline (Sharma et al. 2016).

Tetracycline class acts as protein synthesis inhibitors and the investigation of these compound series helps to understand the underlying mechanism that is involved in the bacterial resistance. The series of the tetracycline compounds could also be improved to understand the underlying mechanisms involved in the progression of bacterial infection and ways to inhibit it through the development of the drugs.

This tetracycline series could be further improved or progressed to the clinical trials as it is a broad spectrum of antibiotics. It has the capacity to alleviate many neurological disorders like multiple sclerosis. This involves the anti-apoptotic effects of tetracycline that can be utilized through randomized control trails. Moreover, doxycycline under tetracycline class can also be improved through gene therapy via plasmid that encodes tumor necrosis factor-alpha for the treatment of arthritis. Tetracycline has poor affinity for 80s eukaryotic ribosomes and weak in inhibiting protein synthesis. Therefore, clinical trials can prove to improve this activity of tetracyclines. It can also be improved and used as tool to study the gene function. Furthermore, it can also be used in clinical trials to study the gene alteration that contribute to the tetracycline expression and related phenotypic consequences. It can be improved to increase the efficiency of the antimicrobials against the gram-negative multidrug-resistant bacteria. It can also be progressed to clinics for studying the development of drug-resistance in bacteria so that it is able to maintain the effectiveness of the antibacterial drugs (Myers et al. 2016).

References

Chang, A.K. and Olshaker, J.S., 2014. Dizziness and vertigo. Rosen's Emergency Medicine: Concepts and Clinical Practice. 8th ed. Philadelphia, PA: Elsevier Mosby.

Daghrir, R. and Drogui, P., 2013. Tetracycline antibiotics in the environment: a review. Environmental Chemistry Letters, 11(3), pp.209-227.

Dubey, K.K., Agrawal, D., Soni, S.L., Namdev, A. and Singh, S.P., 2015. A Review On Oro-Dispersible Doxycycline Tablets Asian Journal of Pharmaceutical Research and Development Vol, 3(6), pp.1-10.

Forsberg, K.J., Patel, S., Wencewicz, T.A. and Dantas, G., 2015. The tetracycline destructases: a novel family of tetracycline-inactivating enzymes. Chemistry & biology, 22(7), pp.888-897.

Marczak, M., Grabowski, T. and Feder, M., 2015. Relationship between Tetracyclines’ Structure and Minimal Inhibitory Concentration of Streptococcus spp. Drug research, 65(08), pp.410-415.

Myers, A.G., Charest, M.G., Lerner, C.D., Brubaker, J.D. and Siegel, D.R., Fellows Of Harvard College, 2016. Synthesis of tetracyclines and analogues thereof. U.S. Patent 9,365,493.

Nguyen, F., Starosta, A.L., Arenz, S., Sohmen, D., Dönhöfer, A. and Wilson, D.N., 2014. Tetracycline antibiotics and resistance mechanisms. Biological chemistry, 395(5), pp.559-575.

Sharma, V.K., Johnson, N., Cizmas, L., McDonald, T.J. and Kim, H., 2016. A review of the influence of treatment strategies on antibiotic resistant bacteria and antibiotic resistance genes. Chemosphere, 150, pp.702-714.

Stone, L.K., Baym, M., Lieberman, T.D., Chait, R., Clardy, J. and Kishony, R., 2016. Compounds that select against the tetracycline-resistance efflux pump. Nature Chemical Biology, 12(11), pp.902-904.

Vedatam, S. and Moller, A.R., 2015. Minocycline: a novel stroke therapy. J Neurol Stroke, 2(6), p.00073.

Zimmermann, L., Das, I., Désiré, J., Sautrey, G., Barros RS, V., El Khoury, M., Mingeot-Leclercq, M.P. and Décout, J.L., 2016. New Broad-Spectrum Antibacterial Amphiphilic Aminoglycosides Active against Resistant Bacteria: From Neamine Derivatives to Smaller Neosamine Analogues. Journal of Medicinal Chemistry, 59(20), pp.9350-9369.