Living Textbook MC610

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They were first isolated from Streptomyces sp. in the late 1940s, with Chlorotetracycline being the first agent isolated. The first agents had comparative low toxicity and a very broad spectrum making them very attractive agents. They are effective against Gram positive, Gram negative, rickettseae, mycobacterium and protozoa. They were widely employed until ß-lactams took over. They remain important agents for specific indications, such as Rocky Mountain spotted fever, Lyme's disease, typhus, acne. They are also employed in many other indications ranging from upper RTI, UTI, ophthalmic infections, sexually transmitted diseases, prophylaxis for malaria, to cholera and tuberculosis. They are also widely used as animal feeds.

Mechanism of Action:

They inhibit protein synthesis, and are thus bacteriostatic.

They inhibit both the 70S and the 80S units, but the former is more sensitive.

They reversibly bind to the smaller unit (30S subunit in bacteria) at the A-site preventing the attachment of the amino acyl tRNA, and leading to the termination of the translation process will take place.

Their selective toxicity is due to in part to their better binding to the 70S ribosomal subunit compared to the 80S ribosomal subunit (imperfect distinction). In addition, these agents seem to be efficiently transported into the bacterial cells but not mammalian cells. They seem to enter through porins in case of Gram negative bacteria and beacuse of their lipophilicity in case of Gram positive bacteria. They can then pass through the cytoplasmic membrane by an energy-requiring active transport, where the bacteria mistaken Tetracyclines for food.

Tetracycline's to chelate divalent cations (see below) may be of significance in determining their effectiveness. Magnesium ions attached to the phosphates on RNA seem to aid in their initial binding to the ribosomes. On the other hand free Magnesium in the cytoplasm will limit their ability to interact with the ribosomes.

Structure Activity Relationship:

In general, no changes can be afforded to the Southern and Eastern portions of the molecules, while changes in the Northern and Western portion will affect activity and pharmacokinetic properties.

So any changes at the 1, 10, 11, 12 and 12a positions will completely abolish activity, even changes in the stereochemical configuration.

2-position, will lead to a decreased activity, even substitution to the amide.

4-position, the amine is essential, but monosubstitution is also active. The amine must be in the α-position.

5-position can have a hydroxyl, keto group or a hydrogen, and all active.

6-position, both substitution are not necessary.

7-position, Cl, F, Br, NO2 and a tertiary amine are all active.

8-position, any electron withdrawing or donating group is still active.

9-position, is recently being studied to overcome bacterial resistance.

Chemical Instability:

  1. In acidic Medium ,
  2. Anhydrotetracycline and its epimer (4-epi-anhydrotetracycline) are formed which can lead to nephrotoxicity (Fanconi's syndrome). This reaction can take place as TCs age, and is accelerated by improper storage.
  3. In basic Medium ,
  4. at pH above 8.5, opening of the third ring will take place, resulting in an inactive lactione, isotetracycline.
  5. In acidic Solution, pH around 4 , epimerization at the 4-position can take place from the α-position to the ί-position, which is inactive. Old TCs capsules were overfilled by about 15% to partially overcome this problem.
  6. Phototoxicity, especially with compounds containing a chloro-substitution at the 7-position, can lead to sunburn due to free radical formations on exposure to sunlight.

Side effects result from imperfect distinguishing the 70S and 80S subunits, thus liver and kidney damage in case of high doses or during pregnancy may occur.

Chemically they have three ionizable groups, the 3-hydroxyl group with a pKa of 2.8 - 3.3, 10-phenolic group with a pKa of 7.2 - 7.8 and the 4-amine with a pKa of 9.1 - 9.7. Their isoelectric point is around 5, thus absorption may be affected by Zwitterion formation.

They can also chelate with metals, such as Magnesium, Calcium, Iron, Aluminum and Zinc, which are insoluble and will affect the absorption of both agents. So avoid taking them with antacids, minerals or milk.

They tend to accumulate in Calcium rich tissues such as bones and teeth. In teeth, they lead to a dose-dependent permanent discoloration, since they are yellow and then transform to a brown color, a photochemical process. Except in extreme cases this is a cosmetic problem, but the teeth retain their properties. They are not recommended for children except in very rare cases (such as Rocky Mountain Spotted Fever).

In IM injectable form, the TCs are coadministered with EDTA (a chelating agent) and buffered at an acidic pH (where the chelation is minimal). This results in less pain upon injection, which is attributed to chelation with Calcium. TCs can also cause thrombophlebitis if injected intravenously. Oral use is the preferred route of administration.

Resistance may arise through production of a protein that prevents binding of TCs to the 30S subunit, or through efflux of the TCs to the outside of the cells. It is currently a wide spread problem that limits the use of TCs.

Individual Agents:

Tetracycline and Oxytetracycline are older agents, comparatively cheap. Their oral bioavailability is often irregular, and is highly affected by food or milk.

Demeclocycline is more chemically stable due to the absence of the 6-methyl group. It is better absorbed than its predecessors.

Minocycline and Doxycycline are semisynthetic products that show a longer t1/2 (due to slower elimination), better stability (due to absence of the 6-hydroxyl group), better tissue penetration and good oral bioavailability (higher lipophilicity), thus the dose given is lower and may allow once or twice a day dosing. They are also less susceptible to chelate formation and show less GIT disturbance.

Tigecycline was recently approved by the FDA, and is touted as a first in a new “class” of antibiotics known as Glycylcyclines. They are less susceptible to resistance compared to other Tetracyclines, and show no cross-resistance with other antimicrobials. The reason these agents are less susceptible to resistance may be due to the fact that efflux systems in some bacteria do not recognize them as unwanted species.  In addition, they bind at least 5 times as tightly to the ribsomes, thus overcoming the effects of the TET proteins.  The 9-glycyl substituent may provide steric hinderness or additional binding sites that may play a role in this latter effect. Tigecycline is used intravenously.