Tetracyclines and their Derivatives: Structure, Activity, Pharmacokinetics, and Toxicity

Tetracyclines are a group of antibiotics characterized by their phenanthrene ring structure. They are known for their bacteriostatic action (except for minocycline, which is bactericidal). This group possesses a broad spectrum of activity, making them effective in treating various bacterial infections.

Structure and Activity:

• Structure: The phenanthrene ring of tetracyclines comprises four rings, with the A/B ring in a cis configuration, C12a bearing an OH group in the alpha direction. The N(CH3)2 group at position C4 is axially oriented.

• Activity: The substituent R on the carboxamic (-CONHR) function of the phenanthrene ring influences tetracycline’s water solubility. Structural alterations affect activity, for instance:

• Minocycline: Contains an additional N,N-dimethylamino group at C7 compared to tetracycline, resulting in stronger bactericidal action.

• Doxycycline: Lacks an OH group at C6, making it stable in the intestinal environment.

Mechanism of Action:

Tetracyclines exert their action by inhibiting bacterial protein synthesis. They accomplish this by binding to the 30S subunit of the bacterial ribosome (RBX).

Pharmacokinetics:

• Absorption: The absorption capacity of cyclines varies: Minocycline > Doxycycline > Tetracycline > Chlortetracycline.

• Distribution: Tetracyclines distribute widely throughout tissues, body fluids, and cross the blood-brain barrier.

• Elimination: Tetracyclines are primarily eliminated via urine, except for minocycline, which is excreted through bile.

Indications and Characteristics:

• Indications:

• Doxycycline: Specifically indicated for treating traveler’s diarrhea and preventing malaria caused by Plasmodium falciparum.

• Tigecycline: The first glycylcycline antibiotic, it possesses a broader spectrum of activity, demonstrating increased sensitivity to tetracycline-resistant bacteria.

• Characteristics:

• Minocycline: Less affected by food and dairy products.

• Doxycycline and minocycline (second generation): Prolonged action, complete absorption through the gut.

Adverse Effects:

• Bone and Tooth Toxicity: Due to the formation of cycline-calcium-orthophosphate complexes, it can cause teeth discoloration, enamel damage, and growth retardation in children.

• Minocycline Toxicity: Can cause vestibular toxicity, dizziness, coordination problems, nausea, and vomiting.

Drug Interactions:

Tetracyclines can interact with various drugs, particularly Rifampicin, phenytoin, barbiturates, decreasing tetracycline’s efficacy by inducing CYP450 activity.

Resistance:

Mechanisms of bacterial resistance to tetracyclines include: antibiotic efflux pumps, protection of the RBX, and oxygen-dependent flavin-monooxygenase enzymes.

Synthesis:

Tetracyclines are produced through a fermentation process, isolated from the culture medium of Streptomyces bacterial strains.

Conclusion:

Tetracyclines represent a crucial group of antibiotics with diverse applications in treating bacterial infections. However, they can induce severe adverse effects, necessitating cautious use and strict adherence to medical prescriptions.