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Protein-synthesis-inhibitors.pptx.......
- 1.
- 2. • A numberof antibiotics exert their antimicrobial effects by targeting the bacterial ribosome • Bacterial ribosome differ structurally the mammalian cytoplasmic ribosome • In general, the bacterial ribosome is smaller (70S) than the mammalian ribosome (80S) and is composed of 50S and 30S subunits (as compared to 60S and 40S subunits)
- 3. • mammalian mitochondrialribosome, however, more closely resembles the bacterial ribosome
- 5. Tetracyclines • Tetracyclines area group of closely related compounds that consist of four fused rings with a system of conjugated double bond. • Subsitution on these rings are responsible for variation in the drug pharmacokinetic.
- 6. Mechanism of action: •Entry into susceptible organisms is mediated both by passive diffusion and by an energy- dependent transport protein mechanism • drug binds reversibly to the 30S subunit of the bacterial ribosome which means a new amino acid can no longer bind to the polypeptide chain. • blocks access of the amino acyl-tRNA to the mRNA-ribosome complex at the acceptor site – inhibiting the bacterial protein synthesis
- 8. • Antibacterial spectrum: •broad-spectrum, bacteriostatic antibiotics • effective against gram-positive and gram-negative bacteria as well as against organisms other than bacteria • Drug of choice against various infections e.g. chlamydial infections (Chlamydia trachomatus), cholera (Vibrio cholera), rocky mountaun spotted fever (Rickettsia reckettsii), Mycoplasma pneumonia
- 9. • Pharmacokinetics: • Alltetracyclines are adequately but incompletely absorbed after oral ingestion • drugs intake with dairy foods in the diet decreases absorption due to the formation of nonabsorbable chelates of the tetracyclines with calcium ions
- 10. • divalent andtrivalent cations (for example, those found in magnesium and aluminum antacids and in iron preparations) also form chelates • This presents the problem if a patient self treats the epigastric pain caused by tetracycline ingestion with antacids.
- 11. • Doxycycline isthe preferred tetracycline for parenteral administration • tetracyclines concentrate in the liver, kidney, spleen, and skin • bind to tissues undergoing calcification (for example, teeth and bones) or to tumors that have a high calcium content (for example, gastric carcinoma)
- 12. • Minocycline entersthe brain and also appears in tears and saliva – however, not effective for central nervous system infections • All tetracyclines cross the placental barrier and concentrate in fetal bones and dentition • parent drug and/or its metabolites are secreted into the bile • Most tetracyclines are reabsorbed in the intestine via the enterohepatic circulation and enter the urine by glomerular filtration
- 13. • doxycycline canbe employed for treating infections in renally compromised patients, because it is preferentially excreted via the bile • Tetracyclines are also excreted in breast milk
- 14. Adverse effects: • Gastricdiscomfort: commonly results from irritation of the gastric mucosa and is often responsible for noncompliance in patients treated with these drugs. • The discomfort can be controlled if the drug is taken with foods other than dairy products
- 15. • Effects oncalcified tissues: Deposition in the bone and primary dentition occurs during calcification in growing children. This causes discoloration and hypoplasia of the teeth and a temporary stunting of growth • Fatal hepatotoxicity: occur in pregnant women who received high doses of tetracyclines • Phototoxicity: severe sunburn occurs when a patient receiving a tetracycline is exposed to sun or ultraviolet rays (Mostly with doxycline)
- 16. • Superinfections: • Overgrowthsof Candida or of resistant staphylococci may occur • Vestibular problems. • Side effect such as dizziness nausea vomiting occur particularly with minocylcline which concentrates in the endolymph of ear and effects function.
- 17. Contraindications • Renally impairedpatients should not be treated with any of the tetracyclines except doxycycline • Accumulation of tetracyclines may aggravate preexisting azotemia • should not be employed in pregnant or breast- feeding women or in children less than 8 years of age
- 18. • Resistance: • inabilityof the organism to accumulate the drug - mediated by the plasmid-encoded resistance protein, TetA • enzymatic inactivation of the drug and production of bacterial proteins that prevent tetracyclines from binding to the ribosome • Any organism resistant to one tetracycline is resistant to all
- 19. Glycylcyclines • Tigecycline, firstavailable member of new class of antimicrobial agent called glycyclines. • It is a derivative of minocycline, is structurally similar to the tetracycline's. • it was developed to overcome the recent emergence of tetracycline resistant organisms
- 20. • Mechanism ofaction Exhibits bacterioststic action y reversibly binding to the 30S ribosomal subunit and inhibit protein translation. It is indicated for treatment of complicated skin and soft tissue infections as well as complicated intra-abdominal infections
- 21. • Antibacterial spectrum: •Tigecycline exhibits expanded broad-spectrum activity including methicillin-resistant staphylococci, multidrug-resistant Streptococcus pneumoniae, and other susceptible strains of streptococcal species, VRE • Also effective against extended-spectrum β- lactamase producing gram-negative bacteria, Acinetobacter baumannii, and many anaerobic organisms
- 22. • Pharmacokinetics: • Administered30- to 60-minute IV infusion every 12 hours • extensively distributed throughout plasma and body tissue • primarily eliminated via biliary/fecal excretion
- 23. • Adverse effects: •adverse effects similar to those of the tetracyclines • photosensitivity, discoloration of permanent teeth when used during tooth development, and fetal harm when administered to a pregnant woman
- 24. Aminoglycosides • Effective forthe treatment of serious infections due to aerobic gram-negative bacilli • use is associated with serious toxicities • use is replaced to some extent by safer antibiotics, such as the third- and fourth- generation cephalosporins, the fluoroquinolones, and the carbapenems
- 25. • Aminoglycosides thatare derived from Streptomyces have -mycin suffixes • those derived from Micromonospora end in –micin • polycationic nature prevent their easy passage across tissue membranes • Aminoglycosides have a hexose ring to which various amino sugars are attached by glycosidic linkages • All aminoglycosides are bactericidal
- 26. • Mechanism ofaction: • Aminoglycosides are irreversible inhibitors of protein synthesis • Organism allow aminogyclosides to diffuse through porin channels in the outer membranes of susceptible microorganism • These organisms also have an oxygen-dependent system that transports the drug across the cytoplasmic membrane • bind to the 30S ribosomal subunit
- 27. • Protein synthesisis inhibited in at least three ways (1) interference with the initiation complex of peptide formation; (2) misreading of mRNA; (3) breakup of polysomes into nonfunctional monosomes • These activities occur simultaneously, and the overall effect is irreversible and lethal for the cell
- 29. • Antibacterial spectrum: •effective in the empirical treatment of infections due to aerobic gram-negative bacilli, including Pseudomonas aeruginosa • Aminoglycosides are often combined with a β- lactam antibiotic, or vancomycin(drug active against aneraobic bacteria) to achieve synergistic effect.
- 30. • Exact mechanismof their lethality is unknown because other antibiotics that inhibit protein synthesis are generally bacteriostatic. • Only effective against aerobic organism because anaerobes lack oxygen requiring drug transport system.
- 31. • Resistance: • 1)decreased uptake of drug when the oxygen- dependent transport system for aminoglycosides or porin channels are absent • 2) plasmid-associated synthesis of enzymes
- 32. • Pharmacokinetics: • Oralabsorption is variable • all aminoglycosides (except neomycin) must be given parenterally to achieve adequate serum levels • Neomycin use is limited to topical application for skin infections or oral administration to prepare the bowel prior to surgery (because of sever nephrotoxicity after parenteral administration)
- 33. • The bactericidaleffect is concentration dependent (greater the conc. of drug, greater the bacteria killing) • Levels achieved in most tissues are low, and penetration into most body fluids is variable • Concentrations in CSF are inadequate • High concentrations accumulate in the renal cortex and in the endolymph and perilymph of the inner ear
- 34. • All aminoglycosidescross the placental barrier and may accumulate in fetal plasma and amniotic fluid • rapidly excreted into the urine
- 35. • Adverse effects: •cause dose-related toxicities • Ototoxicity: (vestibular and cochlear) directly related to high peak plasma levels and the duration of treatment • toxicity correlates with the number of destroyed hair cells in the organ of Corti • Deafness may be irreversible
- 36. • Nephrotoxicity: Retentionby the proximal tubular cells disrupts calcium-mediated transport processes and this result in kidney damage from mild (reversible renal impairment) to sever ( irreversible acute tubular necrosis)
- 37. • Neuromuscular paralysis:occurs after direct intraperitoneal or intrapleural application of large doses of the drugs • administration of calcium gluconate or neostigmine can reverse the block • Allergic reactions: Contact dermatitis is a common reaction to topically applied neomycin
- 38. Macrolides • macrolides area group of antibiotics with a macrocyclic lactone structure to which one or more deoxy sugars are attached • Telithromycin, a semisynthetic derivative of erythromycin, is the first ketolide • Ketolides and macrolides have very similar antimicrobial coverage. However, the ketolides are active against many macrolide-resistant gram-positive strains
- 40. • Mechanism ofaction: • macrolides bind irreversibly to 50S subunit of the bacterial ribosome • Generally bacteriostatic, they may be bactericidal at higher doses • Antibacterial spectrum: • Erythromycin: the spectrum is same as that of penicillin G • used in patients who are allergic to the penicillins
- 41. • Clarithromycin: • effectiveagainst Haemophilus influenzae • activity against intracellular pathogens, such as Chlamydia, Legionella, Moraxella, and Ureaplasma species and Helicobacter pylori, is higher than that of erythromycin
- 42. • Azithromycin: • lessactive against streptococci and staphylococci than erythromycin • far more active against respiratory infections due to H. influenzae and Moraxella catarrhalis • it is now the preferred therapy for urethritis caused by Chlamydia trachomatis. • It also has activity against Mycobacterium avium- intracellulare complex in patients with acquired immunodeficiency syndrome
- 43. • Telithromycin: • hasan antibacterial spectrum similar to that of azithromycin
- 53. • Adverse effects: •Epigastric distress • Cholestatic jaundice • Ototoxicity • Contraindications: in patients with hepatic dysfunction because these drugs accumulate in the liver – hepatotoxicity • Telithromycin is contraindicated in patients with myasthenia gravis
- 54. Chloramphenicol • a broad-spectrumantibiotic, is effective to treat life-threatening infections for which no alternatives exist • Mechanism of action: • binds reversibly to the 50S subunit of the bacterial ribosome and inhibits peptide bond formation • protein synthesis in mitochondria may be inhibited at high circulating chloramphenicol levels, producing bone marrow toxicity
- 56. • Antimicrobial spectrum: •active not only against bacteria but also against other microorganisms, such as Rickettsiae but not Chlamydiae • excellent activity against anaerobes • It is either bactericidal or bacteriostatic, depending on the organism • H influenzae, Neisseria meningitidis , and some strains of bacteroides are highly susceptible, and for these organisms, chloramphenicol may be bactericidal
- 57. • Resistance: • inabilityof the antibiotic to penetrate the organism – basis of multidrug resistance • Clinically significant resistance is due to production of chloramphenicol acetyltransferase, a plasmid-encoded enzyme that inactivates the drug
- 58. • Pharmacokinetics: • administeredeither IV or orally • completely absorbed via the oral route because of its lipophilic nature, and is widely distributed throughout the body • readily enters the normal CSF • inhibits the hepatic mixed-function oxidases • secreted by the renal tubule • also secreted into breast milk
- 59. • Adverse effects: •GIT upsets • overgrowth of Candida albicans on mucous membranes • Anemias: Hemolytic anemia occurs in patients with low levels of glucose 6-phosphate dehydrogenase • aplastic anemia although rare, is idiosyncratic and usually fatal
- 60. • Gray babysyndrome: occurs in neonates if the dosage regimen of chloramphenicol is not properly adjusted • Neonates have a low capacity to metabolize it, and have underdeveloped renal function • The drug accumulates to levels that interfere with the function of mitochondrial ribosomes
- 61. • leads topoor feeding, depressed breathing, cardiovascular collapse, cyanosis, and death • Adults who have received very high doses of the drug can also exhibit this toxicity • Interactions: inhibit hepatic mixed-function oxidases and blocks the metabolism of such drugs as warfarin, phenytoin, tolbutamide, and chlorpropamide
- 62. Clindamycin • Clindamycin isa chlorine-substituted derivative of lincomycin , an antibiotic that is elaborated by Streptomyces lincolnensis . • Mechanism of Action & Antibacterial Activity • inhibits protein synthesis by interfering with the formation of initiation complexes and with aminoacyl translocation reactions
- 63. • binding siteon the 50S subunit is identical with that for erythromycin • employed primarily in the treatment of infections caused by anaerobic bacteria, such as Bacteroides fragilis, which often causes abdominal infections associated with trauma • Also inhibits Streptococci, staphylococci, and pneumococci • Enterococci and gramnegative aerobic organisms are resistant.
- 64. • Clostridium difficileis always resistant to clindamycin • Pharmacokinetics: • well absorbed by the oral route • distributes well into all body fluids except the CSF • undergoes extensive oxidative metabolism to inactive products in the liver • excreted into the bile or urine by glomerular filtration
- 65. • Resistance mechanisms: •(1) mutation of the ribosomal receptor site • (2) modification of the receptor by a constitutively expressed methylase • (3) enzymatic inactivation of clindamycin • Adverse effects: • potentially fatal pseudomembranous colitis caused by overgrowth of C. difficile which secretes necrotizing toxins
- 66. Quinupristin/Dalfopristin • combination oftwo streptogramins antibiotics used to treat infections by staphylococci and by vancomycin resistant Enterococcus faecium • combined in a weight-to-weight ratio of 30% quinupristin to 70% dalfopristin - derived from a streptomycete and then chemically modified • Mechanism of action: • They are protein synthesis inhibitors in a synergistic manner
- 67. • While eachof the two is only a bacteriostatic agent, the combination shows bactericidal activity • Dalfopristin binds to the 50S ribosomal subunit, and changes the conformation of it, enhancing the binding of quinupristin by a factor of about 100 • Dalfoprisitin inhibits peptidyl transfer
- 68. • Quinupristin bindsto a nearby site on the 50S ribosomal subunit and prevents elongation of the polypeptide as well as causing incomplete chains to be released • drug is not effective against Enterococcus faecalis • Pharmacokinetics • Administered IV in a 5 % dextrose solution (the drug is incompatible with a saline medium)
- 69. • penetrates macrophagesand polymorphonucleocytes • parent drugs and metabolites are cleared through the liver and eliminated via the bile • Adverse effects: • Joint aches (arthralgia) or muscle aches (myalgia) • Nausea, diarrhea or vomiting • Rash or itching • Headache • Phlebitis • Hyperbilirubinemia
- 70. • Resistance: • Plasmid-associatedacetyltransferase inactivates dalfopristin. An active efflux pump can also decrease levels of the antibiotics in bacteria • Drug interactions • inhibit the cytochrome P450
- 71. Linezolid • Linezolid isa totally synthetic antibiotic • It was introduced recently to combat resistant gram-positive organisms • Effective against methicillin- and vancomycin- resistant Staphylococcus aureus, vancomycin- resistant E. faecium and E. faecalis, and penicillin-resistant streptococci
- 72. • Mechanism ofaction: • inhibits bacterial protein synthesis by inhibiting the formation of the 70S initiation complex • binds to a site on the 50S subunit near the interface with the 30S subunit • Antibacterial spectrum: • Effective against staphylococci, streptococci, and enterococci, as well as Corynebacterium species and Listeria monocytogenes
- 73. • moderately activeagainst Mycobacterium tuberculosis • It is bacteriostatic • Pharmacokinetics: • completely absorbed on oral administration – IV preparation is also available • widely distributed throughout the body • Drug and metabolites are excreted both by renal and nonrenal routes
- 74. • Adverse effects: •Nausea and diarrhea • headaches • Rash • Thrombocytopenia