PHL 424 Antimicrobials 2nd Lecture By Abdelkader Ashour, Ph.D. Phone: 4677212 Email: aeashour@ksu.edu.sa

Inhibitors of bacterial protein synthesis, Tetracyclines Tetracyclines are safe, inexpensive broad- spectrum bacteriostatic antibiotics that inhibit protein synthesis The basic tetracycline structure consists of four benzene rings with various substituent on each ring (C22H24N2O8; M.Wt. 444.43)

Inhibitors of bacterial protein synthesis, Tetracyclines Tetracyclines are classified as: Short-acting: This includes oxytetracycline (a natural product produced by Streptomyces rimosus) & tetracycline (a semisynthetic derivative of chlortetracycline, produced by Streptomyces aureofaciens Intermediate acting: This includes demeclocycline (the product of a mutant strain of Strep. Aureofaciens) and methacycline (semisynthetic) Long-acting, e.g., doxycycline and minocycline which are semisynthetic derivatives The almost complete absorption and slow excretion of doxycycline and minocycline allow for once-daily dosing A newly approved tetracycline analog, tigecycline, Is a semisynthetic derivative of minocycline

Inhibitors of bacterial protein synthesis, Tetracyclines, contd. MOA: Tetracyclines enter microorganisms through cell wall in part by passive diffusion and in part by an energy-dependent process of active transport Susceptible cells concentrate the drug intracellularly Tetracyclines then bind reversibly to the 30S subunit of the bacterial ribosome, blocking the binding of aminoacyl-tRNA to the acceptor site on the mRNA-ribosome complex This prevents addition of amino acids to the growing peptide, with subsequent inhibition of protein synthesis

Inhibitors of bacterial protein synthesis, Tetracyclines, contd. Antimicrobial actions: Tetracyclines are active against many G+ve & G-ve bacteria, including anaerobes, rickettsiae, chlamydiae, mycoplasmas Minocycline is usually the most active followed by doxycycline They are also active against some protozoa, e.g., amebas The antibacterial activities of most tetracyclines are similar except that tetracycline-resistant strains may remain susceptible to doxycycline or minocycline, drugs that are less rapidly transported by the pump that is responsible for resistance Resistance mechanisms : Decreased intracellular accumulation due to either decreased influx or increased efflux by an active transport protein pump … (the most important) Ribosome protection due to production of proteins that interfere with tetracycline binding to the ribosome Enzymatic inactivation of tetracyclines Resistance is primarily plasmid-mediated and often is inducible

Inhibitors of bacterial protein synthesis, Tetracyclines, contd. Pharmacokinetics Substitutions on these rings are responsible for variation in the drugs‘ individual pharmacokinetics. Thus tetracyclines mainly differ in their absorption after oral administration and their elimination, causing small differences in their clinical efficacy Absorption after oral administration is approximately 30% for chlortetracycline; 60– 70% for tetracycline, oxytetracycline, demeclocycline, and methacycline; and 95– 100% for doxycycline and minocycline A portion of an orally administered dose of tetracycline remains in the gut lumen, modifies intestinal flora, and is excreted in the feces Absorption occurs mainly in the upper small intestine and is impaired by food (except doxycycline and minocycline); by divalent cations (Ca2+, Mg2+, Fe2+) or Al3+; by dairy products and antacids, which contain multivalent cations, …..so! The decreased absorption results from chelation of divalent and trivalent cations Tetracyclines are 40–80% bound by plasma proteins. They are distributed widely to tissues and body fluids except for CSF (levels are 10–25% of those in serum) Minocycline reaches very high concentrations in tears and saliva, which makes it useful for eradication of the meningococcalcarrier state

Inhibitors of bacterial protein synthesis, Tetracyclines, contd. Pharmacokinetics, contd. Tetracyclines cross the placenta to reach the fetus and are also excreted in milk. As a result of chelation with calcium, tetracyclines are bound to—and damage—growing bones and teeth Tetracyclines are excreted mainly in urine (mainly by glomerular filtration) and bile; Small % of the these drugs are excreted in feces. Some of the drug excreted in bile is reabsorbed from the intestine (enterohepatic circulation) and contributes to maintenance of serum levels Doxycycline, in contrast to other tetracyclines, is eliminated by nonrenal mechanisms (excreted in feces), does not accumulate significantly in renal failure, and requires no dosage adjustment, making it the tetracycline of choice for use in the setting of renal insufficiency Minocycline is recovered from urine and feces in significantly lower amounts than are the other tetracyclines, and it appears to be metabolized to a considerable extent Its renal clearance is low. The drug persists in the body long after its administration is stopped, possibly due to retention in fatty tissues. Nonetheless, its half-life is not prolonged in patients with hepatic failure