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1997 Clinical pharmacology By Duy Thai

ANTIBIOTICS 2 Drugs acting on protein synthesis • Protein synthesis in bacteria occur in 3 steps: 1. Recognition • Requires G factors and GTP as the energy molecule • The 50S subunit of the ribosome contains a P site and an A site. The A site is the one which receives the next tRNA carrying a particular amino acid. • Which tRNA comes along is determined by the codon on the mRNA. The tRNA contains an anticodon which matches the codon on the mRNA strand 2. Peptidyl transfer • A tRNA molecule on the P site has got a growing peptide chain. The new tRNA in the A site will add another amino acid to this growing chain. • What happens is that the peptide chant on the tRNA at the P site is stuck onto the amino acid on the tRNA at the A site via peptidyl transferase. • The tRNA at the P site then goes away 3. Translocation • Requires G factor and GTP • The ribosome then moves to the next codon. • In so doing, the tRNA which was in the A site, is now located on the P site. • The whole thing repeats itself: another tRNA comes into the A site, and the peptide chain is added to the new amino acid • Various antibiotics have been developed to disrupt this 3 step process.

Sites of action: Recognition • Aminoglycosides • E.g Streptomycin, gentamycin • Highly charged, therefore not well absorbed and has to be injected. • Bactericidal • Bind to the 30s unit of the ribosome and distorts the reading frame. • Protein synthesis can still continue, but distortion results in either misense or nonsense codons leading to the wrong ammo acid being used and premature termination • The proteins produced by the bacteria are required in maintaining cell intergrity. If inhibited, the cell wall becomes damaged • Damage to the cell wall results in aminoglycosides being able to enter the cell freely. • Aminoglycosides are highly charged molecules, and hence cannot pass through the cell membrane easily. They rely on a small number being able to enter the cell and disrupt cell integrity, thus allowing heaps more to pour in and wreak heaps of damage. • Under anaerobic conditions, aminoglycosides are highly charged, and therefore will be unable to work. Hence, anaerobic bacteria tend to be more resistant to aminoglycosides. Some bacteria have anaerobic metabolism (e.g. Streptococci and are also resistant) • Because the cell membrane is such a big barrier, aminoglycosides do not work against obligate intracellular bacteria (e.g. Chlamydia, Rickettsia) They can work against facultative intracellullar bacteria which have an extracellular phase (e.g. Mycobacteriam tuberculosis) • Resistance can occur by bacteria altering the 30s ribosome binding site of the drug. • Often, aminoglycosides and beta lactams are used in conjunction because they have a synergistic effect. Beta lactams can inhibit the production of the cell wall, producing a weakened cell wall which allows aminoglycosides to enter more easily in higher concentrations. The time to kill the bacteria is thus reduced

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1997 Clinical pharmacology By Duy Thai

Tetracyclines • e.g. doxycycline minocycline • Can work on G- and G+ bacteria • Drug of choice for Rickettsia infections • Thought to interfere with the energy released by T factors • Binds to the 30s subunit and prevents the binding of tRNA to the A site • The effect is reversible, so it acts as a bacteristatic agent. • Not used in pregnancy because the drug can deposit in teeth of foetus and young children.

Sites of action: Peptidy transfer • 2 groups of drugs acting on peptidyl transferase 1. Chloramphenicol • Used to treat Hib, typhoid fever, Rickettsia • Binds to the 50S subunit and blocks the action of peptidyl transferase • Bactericidal to 3 important organisms: • Hemophylus influenzae • Streptococcus pneumoniae • Neisseria meningitides 2. CIindamycin • Bad reputation • Often used excessively to treat G- anaeroboes, however, in so doing, it will also kill off many G- bacteria in our gut. This allows Clostridium difficile (resistant) to grow, causing pesudomembranous colitis. • Competes with chloramphenicol to bind to peptidyl transferase, hence the 2 drugs act as competitive antagonists. • Mainly used topically for treatment of acne

Site of action: Translocation • Macrolides • e.g. Erythromycin • Few side effects • Safe to give in pregnancy • Good for bacteria associated with atypical pneumonia (e.g. with mycoplasma, leigonella) • By altering the side chains, you can produce a macrolide with improved spectrum and better pharmacokinetics (e.g. clarithromycin, azithromycin) • It acts by binding to the 50S subunit between the A and P sites, physically interfering with the translocation step. • The binding is irreversible hence it is a bacteristatic agent. • Fusidic acid • A steroid • Interferes with G factor involved in the translocation step Drugs acting on nucleic acid metabolism • 5 fluorocytosine • Given as a prodrug • It is activated by cytosine deaminase which is present in fungi (hence it is antifungal) • Its active form is 5 fluorouracil • Metronidazole • Given as an inactive form. It is activated by nitro reductase (present in anaerobic bacteria to break down oxygen)

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1997 Clinical pharmacology By Duy Thai

Quinolones • e.g. Nalidixic acid • Interferes with gyrase, which is involved in folding of the bacterial chromosome. • It is secreted unchanged in the urine, and hence it is effective against urinary tract infections. • By adding an extra FIuoride, you get Ciprofloxacin which can be used to treat more systemic infections. It has a broader spectrum and is antimycobacterial and pseudomonas. Rifampicin • Inhibits the bacterial for of RNA polymerase • Drug of choice for treating TB • Broad spectrum, can be used against G-ve, G+ rods and cocci. Also antiviral • If used to treat trivial infections, and the person has latent TB, then the low doses may get rid of the trivial infection but may result in the formation of resistant TB. Therefore, when the TB flares up again, it will be very difficult to treat.

Drugs affecting vitamin metabolism • Bacteria are able to synthesise folic acid from pABA However, we are unable to synthesis folic acid and must get it from our diet. • Sulphonamides • Analogue of pABA • Interferes with the uptake of pABA into the bacteria and also interferes with the first step of tetrahydrofolate production pABA + pteridine) • If sulphonamides are added bacterial growth does not stop immediately because the bacteria have folic acid stores Trimethoprim • Inhibits the enzyme dihydrofolate reductase, which is involved in the synthesis of tetrahydrofolate. • Present in both humans and bacteria, although trimethoprim is selective for the bacterial form. • Methotrexate is selective for the human form, and is used in cancer therapy. • Often given in conjunction with sulphonamides (cotrimoxazole) - trimethoprim + sulphonamide. • There is no evidence that these drugs have any real synergistic effect, because by blocking the first step, there is no real reason to block further steps. However, there may be some molecules which can leak past the initial blockage. and so this may be the rationale for this. Izoniazid • Bactericidal • An analogue of pyridoxine • A prodrug which is converted to its active form by Mycobacterium (therefore it is highly specific for these bacteria) • It interferes with pyridoxine metabolism

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