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DNA. . RNA. . . RNA Polymerase. Ribosome. . Protein. . . . . . . Cell wall. Replication. Cell Wall SynthesisProteins. The Central Dogma. DNA Replication InhibitorsRNA Polymerase Inhibition Translation InhibitorsMetronidazole. Lecture Plan. SulfonamidesTrimethoprimQuinolines. DNA Synthesis Inhibitors.
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1. Mechanisms of Antibiotic Function-II We have completed our study of mechanisms of cell wall synthesis inhibitor.
Today we will focus on mechanisms of action of most of the other groups of antibioticsWe have completed our study of mechanisms of cell wall synthesis inhibitor.
Today we will focus on mechanisms of action of most of the other groups of antibiotics
2. The Central Dogma We stated that the best antibiotic is one that has little or no toxicity to humans, yet is highly specific to the disease causing microbe.
Besides cell wall maintenance or generation, any of the major mechanisms involved in a cells survival can be targeted as long as we fulfill our requirement above.
This includes DNA replication without which cells can not replicate. This can be done by inhibiting nucleic acid synthesis for example. It also includes transcription, the generation of RNA, without which no protein can be produced.
Targeting the the translation machinery and its Ribosome motor also could prevent or disrupt the generation of protein.
Although proteins structures and most mechanisms of the central dogma are conserved from bacteria to man, never-the less, pronounced differences exist. These allow for drugs that can target bacterial processes with limited affect on humans.We stated that the best antibiotic is one that has little or no toxicity to humans, yet is highly specific to the disease causing microbe.
Besides cell wall maintenance or generation, any of the major mechanisms involved in a cells survival can be targeted as long as we fulfill our requirement above.
This includes DNA replication without which cells can not replicate. This can be done by inhibiting nucleic acid synthesis for example. It also includes transcription, the generation of RNA, without which no protein can be produced.
Targeting the the translation machinery and its Ribosome motor also could prevent or disrupt the generation of protein.
Although proteins structures and most mechanisms of the central dogma are conserved from bacteria to man, never-the less, pronounced differences exist. These allow for drugs that can target bacterial processes with limited affect on humans.
3. Lecture Plan Lets start with Inhibitors of the translation machinery.
We are now going to look at how transcription proceeds and how antibiotics affect it.
The motor of translation is a very large structure composed of RNA and Protein called the ribosome.
Lets start with Inhibitors of the translation machinery.
We are now going to look at how transcription proceeds and how antibiotics affect it.
The motor of translation is a very large structure composed of RNA and Protein called the ribosome.
4. DNA Synthesis Inhibitors We are now going to briefly review antibiotics which inhibit DNA replication.We are now going to briefly review antibiotics which inhibit DNA replication.
5. DNA Synthesis Inhibitors Sulfonamides inhibit the synthesis of dihydrofolate (DHFA), which is an early step in the pathway of purine and therefore DNA synthesis. Trimephoprim inhibits the following enzymatic reaction that generates tetrahydrofolate sfrom dihydrofolate.
Sulfonamides
Sulfonomides are effective for bacteria that require extracellular PABA for the synthesis of dihydrofolic acid and eventually nucleic acids. They are PABA analogues and reversible inhibitors. They are also bacteriostatic and not bactericidal.
Uses: ALMOST SOLELY IN OUTPATIENTS. both gram +/- bacteria, nocardia, and some protozoa. Note: rickettsiae are actually stimulated in growth by sulfonomides!
Sulfonamides inhibit the synthesis of dihydrofolate (DHFA), which is an early step in the pathway of purine and therefore DNA synthesis. Trimephoprim inhibits the following enzymatic reaction that generates tetrahydrofolate sfrom dihydrofolate.
Sulfonamides
Sulfonomides are effective for bacteria that require extracellular PABA for the synthesis of dihydrofolic acid and eventually nucleic acids. They are PABA analogues and reversible inhibitors. They are also bacteriostatic and not bactericidal.
Uses: ALMOST SOLELY IN OUTPATIENTS. both gram +/- bacteria, nocardia, and some protozoa. Note: rickettsiae are actually stimulated in growth by sulfonomides!
6. Sulfonamides Sulfonamides inhibit the synthesis of dihydrofolate (DHFA), which is an early step in the pathway of purine and therefore DNA synthesis. Trimephoprim inhibits the following enzymatic reaction that generates tetrahydrofolate sfrom dihydrofolate.
Sulfonamides
Sulfonomides are effective for bacteria that require extracellular PABA for the synthesis of dihydrofolic acid and eventually nucleic acids. They are PABA analogues and reversible inhibitors. They are also bacteriostatic and not bactericidal.
Uses: ALMOST SOLELY IN OUTPATIENTS. both gram +/- bacteria, nocardia, and some protozoa. Note: rickettsiae are actually stimulated in growth by sulfonomides!
Sulfonamides inhibit the synthesis of dihydrofolate (DHFA), which is an early step in the pathway of purine and therefore DNA synthesis. Trimephoprim inhibits the following enzymatic reaction that generates tetrahydrofolate sfrom dihydrofolate.
Sulfonamides
Sulfonomides are effective for bacteria that require extracellular PABA for the synthesis of dihydrofolic acid and eventually nucleic acids. They are PABA analogues and reversible inhibitors. They are also bacteriostatic and not bactericidal.
Uses: ALMOST SOLELY IN OUTPATIENTS. both gram +/- bacteria, nocardia, and some protozoa. Note: rickettsiae are actually stimulated in growth by sulfonomides!
7. Resistance: Mammalian cells and some bacteria depend on exogenous folate and are therefore resistant. Also bacteria can overproduce PABA, loss of permeability to PABA or they produce an enzyme with low affinity to PABA.
Distribution is throughout including CNS and fetus. Sulfonamides are altered in the liver and excreted into the urine.
They are divided into groups:
A. oral absorbable agents: Sulfisoxazole and sulfamethoxazole short-medium acting used for urinary tract infections.
B. Nonabsorbable oral agents: used for ulcers and inflammatory bowel. It is sold as Sulfasalazine, split in the intestine to yield 5-aminosalicylate (5-ASA, an anti-inflamation drug) and sulfapyridine.
Adverse reactions: Allergy, Johnson syndrome which can be fatal.. A skin and mucous membrane eruption condition. Also arthritis psychosis, conjunctivitis and more. Crystaluria occurs in high doses, treated with sodium bicarbonate to alkalize the urine. Also observed are hemolytic or aplastic anemia and especially in patients deficient in glucose-6-phosphate dehydrogenase.
Resistance: Mammalian cells and some bacteria depend on exogenous folate and are therefore resistant. Also bacteria can overproduce PABA, loss of permeability to PABA or they produce an enzyme with low affinity to PABA.
Distribution is throughout including CNS and fetus. Sulfonamides are altered in the liver and excreted into the urine.
They are divided into groups:
A. oral absorbable agents: Sulfisoxazole and sulfamethoxazole short-medium acting used for urinary tract infections.
B. Nonabsorbable oral agents: used for ulcers and inflammatory bowel. It is sold as Sulfasalazine, split in the intestine to yield 5-aminosalicylate (5-ASA, an anti-inflamation drug) and sulfapyridine.
Adverse reactions: Allergy, Johnson syndrome which can be fatal.. A skin and mucous membrane eruption condition. Also arthritis psychosis, conjunctivitis and more. Crystaluria occurs in high doses, treated with sodium bicarbonate to alkalize the urine. Also observed are hemolytic or aplastic anemia and especially in patients deficient in glucose-6-phosphate dehydrogenase.
8. Sulfonomides Resistance: Mammalian cells and some bacteria depend on exogenous folate and are therefore resistant. Also bacteria can overproduce PABA, loss of permeability to PABA or they produce an enzyme with low affinity to PABA.
Distribution is throughout including CNS and fetus. Sulfonamides are altered in the liver and excreted into the urine.
They are divided into groups:
A. oral absorbable agents: Sulfisoxazole and sulfamethoxazole short-medium acting used for urinary tract infections.
B. Nonabsorbable oral agents: used for ulcers and inflammatory bowel. It is sold as Sulfasalazine, split in the intestine to yield 5-aminosalicylate (5-ASA, an anti-inflamation drug) and sulfapyridine.
Adverse reactions: Allergy, Johnson syndrome which can be fatal.. A skin and mucous membrane eruption condition. Also arthritis psychosis, conjunctivitis and more. Crystaluria occurs in high doses, treated with sodium bicarbonate to alkalize the urine. Also observed are hemolytic or aplastic anemia and especially in patients deficient in glucose-6-phosphate dehydrogenase.
Resistance: Mammalian cells and some bacteria depend on exogenous folate and are therefore resistant. Also bacteria can overproduce PABA, loss of permeability to PABA or they produce an enzyme with low affinity to PABA.
Distribution is throughout including CNS and fetus. Sulfonamides are altered in the liver and excreted into the urine.
They are divided into groups:
A. oral absorbable agents: Sulfisoxazole and sulfamethoxazole short-medium acting used for urinary tract infections.
B. Nonabsorbable oral agents: used for ulcers and inflammatory bowel. It is sold as Sulfasalazine, split in the intestine to yield 5-aminosalicylate (5-ASA, an anti-inflamation drug) and sulfapyridine.
Adverse reactions: Allergy, Johnson syndrome which can be fatal.. A skin and mucous membrane eruption condition. Also arthritis psychosis, conjunctivitis and more. Crystaluria occurs in high doses, treated with sodium bicarbonate to alkalize the urine. Also observed are hemolytic or aplastic anemia and especially in patients deficient in glucose-6-phosphate dehydrogenase.
9. Trimethoprim Trimethoprim a benzylpyrimidine, inhibits DHFA reductase 50,000 times more than the human enzyme. Taken alone or with sulfonamides.
Resistance: reduced cell permeability, overproduction of DHFA reductase or use of an altered reductase. Resistance is plasmid encoded and rapidly disseminated on conjugative plasmids with a broad host range.
Enters CNS and are excreted in the urine. It concentrates in the prostatic and vaginal fluid and therefore useful.
Uses: Oral trimethoprim: acute urinary tract infections. Trimethoprim-Sulfamethoxazole Mix: Urinary tract infections and much more.
Adverse effects of trimethoprim: typical antifolate drug efects, Megaloblastic anemia, leukopenia and granulocytopenia which is absent when administering folinic acid.
Trimethoprim a benzylpyrimidine, inhibits DHFA reductase 50,000 times more than the human enzyme. Taken alone or with sulfonamides.
Resistance: reduced cell permeability, overproduction of DHFA reductase or use of an altered reductase. Resistance is plasmid encoded and rapidly disseminated on conjugative plasmids with a broad host range.
Enters CNS and are excreted in the urine. It concentrates in the prostatic and vaginal fluid and therefore useful.
Uses: Oral trimethoprim: acute urinary tract infections. Trimethoprim-Sulfamethoxazole Mix: Urinary tract infections and much more.
Adverse effects of trimethoprim: typical antifolate drug efects, Megaloblastic anemia, leukopenia and granulocytopenia which is absent when administering folinic acid.
10. Trimethoprim 2 Trimethoprim a benzylpyrimidine, inhibits DHFA reductase 50,000 times more than the human enzyme. Taken alone or with sulfonamides.
Resistance: reduced cell permeability, overproduction of DHFA reductase or use of an altered reductase. Resistance is plasmid encoded and rapidly disseminated on conjugative plasmids with a broad host range.
Enters CNS and are excreted in the urine. It concentrates in the prostatic and vaginal fluid and therefore useful.
Uses: Oral trimethoprim: acute urinary tract infections. Trimethoprim-Sulfamethoxazole Mix: Urinary tract infections and much more.
Adverse effects of trimethoprim: typical antifolate drug efects, Megaloblastic anemia, leukopenia and granulocytopenia which is absent when administering folinic acid.
Trimethoprim a benzylpyrimidine, inhibits DHFA reductase 50,000 times more than the human enzyme. Taken alone or with sulfonamides.
Resistance: reduced cell permeability, overproduction of DHFA reductase or use of an altered reductase. Resistance is plasmid encoded and rapidly disseminated on conjugative plasmids with a broad host range.
Enters CNS and are excreted in the urine. It concentrates in the prostatic and vaginal fluid and therefore useful.
Uses: Oral trimethoprim: acute urinary tract infections. Trimethoprim-Sulfamethoxazole Mix: Urinary tract infections and much more.
Adverse effects of trimethoprim: typical antifolate drug efects, Megaloblastic anemia, leukopenia and granulocytopenia which is absent when administering folinic acid.
11. Quinolones DNA Gyrase Inhibitors A very important class of antibiotics! Such as Cipro
Quinolones are topoisommerase II (DNA gyrase) and topoIV inhibitors. Inhibition of bacterial DNA gyrase prevents the relaxation of supercoiled DNA required for transcription and replication. Topo IV inhibition inerferes with separation of chromosomal DNA into daughter cells. They are nontoxic well tolerated
The nonflourinated quinolones,such as Nalidixic acid did not achieve systemic antibacterial levels and are not commonly used. The flourinated forms: flouroquinolones are much improved and are are useful systemically.
Uses: Gram - aerobic bacteria. Urinary tract infections caused by multidrug-resistant bacteria and for soft tissue. Levofloxacin with enhanced gram + activity may be used for pneumonia (inclulding chlamydia, mycoplasma and legionella). This is important becaause cephalosporins do not get the atypicals.
Resistance is by one or more point mutations in the quinolone binding region of the target enzyme or to a change in permeability of the organism. Cross resistance exists.
Pharma: Well absorbed. Mostly renal clearance so keep an eye on creatinine.
Uses: Excellent against gram - aerobic bacteria. Only newer derivatives are useful for gram positive cocci.A very important class of antibiotics! Such as Cipro
Quinolones are topoisommerase II (DNA gyrase) and topoIV inhibitors. Inhibition of bacterial DNA gyrase prevents the relaxation of supercoiled DNA required for transcription and replication. Topo IV inhibition inerferes with separation of chromosomal DNA into daughter cells. They are nontoxic well tolerated
The nonflourinated quinolones,such as Nalidixic acid did not achieve systemic antibacterial levels and are not commonly used. The flourinated forms: flouroquinolones are much improved and are are useful systemically.
Uses: Gram - aerobic bacteria. Urinary tract infections caused by multidrug-resistant bacteria and for soft tissue. Levofloxacin with enhanced gram + activity may be used for pneumonia (inclulding chlamydia, mycoplasma and legionella). This is important becaause cephalosporins do not get the atypicals.
Resistance is by one or more point mutations in the quinolone binding region of the target enzyme or to a change in permeability of the organism. Cross resistance exists.
Pharma: Well absorbed. Mostly renal clearance so keep an eye on creatinine.
Uses: Excellent against gram - aerobic bacteria. Only newer derivatives are useful for gram positive cocci.
12. Many Quinolones Quinolones can be divided into classes according to their antibacterial activity as shown in the image.
Group I not used much
Group II is useful. These drugs are well tolerated and broad spectrum. Great for gram - and good for gram +. Quinolones can be divided into classes according to their antibacterial activity as shown in the image.
Group I not used much
Group II is useful. These drugs are well tolerated and broad spectrum. Great for gram - and good for gram +.
13. Many Quinolones Quinolones can be divided into classes according to their antibacterial activity as shown in the image.
Group I not used much
Group II is useful. These drugs are well tolerated and broad spectrum. Great for gram - and good for gram +. Quinolones can be divided into classes according to their antibacterial activity as shown in the image.
Group I not used much
Group II is useful. These drugs are well tolerated and broad spectrum. Great for gram - and good for gram +.
14. Many Quinolones
15. RNA Polymerase Inhibitor: Rifampin Another mechanism for antibiotic development is transcription in that RNA polymerase, which generates all the cellular mRNA is inhibited.
Rifampin a TB drug, inhibits bacterial RNA polymerase but not of eukaryotes. Although both pro and eukaryote polymerases have a similar structure as we can see in the image, the rifampin binding pocket is different leading to specificity.
There will be a lecture on TB so will stop here.Another mechanism for antibiotic development is transcription in that RNA polymerase, which generates all the cellular mRNA is inhibited.
Rifampin a TB drug, inhibits bacterial RNA polymerase but not of eukaryotes. Although both pro and eukaryote polymerases have a similar structure as we can see in the image, the rifampin binding pocket is different leading to specificity.
There will be a lecture on TB so will stop here.
16. Inhibitors of Translation The major groups of ribosome inhibitors are listed in the figure. The major groups of ribosome inhibitors are listed in the figure.
17. Structures of the Prokaryotic and Eukaryotic Ribosome Although bacterial and human ribosomes share homology, they differ in some of their detailed structure such that inhibitors can be selective to bacteria.
Ribosomes are composed of a small and large subunit measured by S (Svedbergs) which is a measurement with components of size and shape such that the 2 bacterial subunits of 30 and 50S when combined are 70S.
We will be talking about the bacterial Ribosome. There are 31 polypeptides and 2 ribosomal RNA molecules (rRNA) in the large subunit and 21 polypeptides and one rRNA in the small subunit.
Although bacterial and human ribosomes share homology, they differ in some of their detailed structure such that inhibitors can be selective to bacteria.
Ribosomes are composed of a small and large subunit measured by S (Svedbergs) which is a measurement with components of size and shape such that the 2 bacterial subunits of 30 and 50S when combined are 70S.
We will be talking about the bacterial Ribosome. There are 31 polypeptides and 2 ribosomal RNA molecules (rRNA) in the large subunit and 21 polypeptides and one rRNA in the small subunit.
18. Structure of the Ribosome The structure of the ribosome was one of this generations major achievements and took over 20 years.
Knowing the precise position of each of the ribosome components, determining the precise location of antibiotic binding, and visualizing the location of the RNA to be translated and the tRNA was a major advancement to both basic science and pharmacology.
By knowing the precise interactions of inhibitors and ribosome we can now design more powerful drugs then ever before. This though is beyond the scope of the lecture.The structure of the ribosome was one of this generations major achievements and took over 20 years.
Knowing the precise position of each of the ribosome components, determining the precise location of antibiotic binding, and visualizing the location of the RNA to be translated and the tRNA was a major advancement to both basic science and pharmacology.
By knowing the precise interactions of inhibitors and ribosome we can now design more powerful drugs then ever before. This though is beyond the scope of the lecture.
19. Ribosomes, Polyribosomes and the Polypeptide Product In bacteria messenger RNA (mRNA) can be translated by many ribosomes at once. This is called a polyribosome.
In the image we see an electron micrograph image of a polyribosome and a polyribosome with its polypeptide products. In bacteria messenger RNA (mRNA) can be translated by many ribosomes at once. This is called a polyribosome.
In the image we see an electron micrograph image of a polyribosome and a polyribosome with its polypeptide products.
20. mRNA and tRNA and A.A. There are three more major players in the protein synthesis pathway. Those are the 20 Amino Acids which comprise the proteins, transfer RNA (tRNA) and messenger RNA (mRNA).
Each amino acid has a one or more specific tRNAs that it will covalently link by an enzymatic reaction that we will briefly discuss. The result is a charged tRNA. The tRNA has a very specific structure which is recognized by the ribosome.
Three bases at the bottom of the tRNA can form specific hydrogen bonds with three bases of the mRNA. This gives rise to the 3 base codon that we should be aware of.There are three more major players in the protein synthesis pathway. Those are the 20 Amino Acids which comprise the proteins, transfer RNA (tRNA) and messenger RNA (mRNA).
Each amino acid has a one or more specific tRNAs that it will covalently link by an enzymatic reaction that we will briefly discuss. The result is a charged tRNA. The tRNA has a very specific structure which is recognized by the ribosome.
Three bases at the bottom of the tRNA can form specific hydrogen bonds with three bases of the mRNA. This gives rise to the 3 base codon that we should be aware of.
21. Three Stages of Translation Translation involves the decoding of mRNA and the resultant generation of a polypeptide chain that folds into a functional protein. Without proteins life can not be sustained.
There are three stages of translation: Initiation, Elongation and Termination.Translation involves the decoding of mRNA and the resultant generation of a polypeptide chain that folds into a functional protein. Without proteins life can not be sustained.
There are three stages of translation: Initiation, Elongation and Termination.
22. Initiation Initiation of Translation involves 4 stages:
1. Met-tRNA & GTP & initiation factor.
2. Met-tRNA added to small ribosomal subunit,
3. Small subunit binds mRNA, a reaction driven by ATP hydrolysis, attachment on the 5 of mRNA of a formyl group resulting in N-formyl-methionine and scans until the start AUG codon.
4. Large ribosomal unit is then added.
There are two sites on the ribosome P and A. An additional site E or exit site exists, but for our purposes we will discuss the P and A site. The complex is formed in the P-site.Initiation of Translation involves 4 stages:
1. Met-tRNA & GTP & initiation factor.
2. Met-tRNA added to small ribosomal subunit,
3. Small subunit binds mRNA, a reaction driven by ATP hydrolysis, attachment on the 5 of mRNA of a formyl group resulting in N-formyl-methionine and scans until the start AUG codon.
4. Large ribosomal unit is then added.
There are two sites on the ribosome P and A. An additional site E or exit site exists, but for our purposes we will discuss the P and A site. The complex is formed in the P-site.
23. Initiation Initiation of Translation involves 4 stages:
1. Met-tRNA & GTP & initiation factor.
2. Met-tRNA added to small ribosomal subunit,
3. Small subunit binds mRNA, a reaction driven by ATP hydrolysis, attachment on the 5 of mRNA of a formyl group resulting in N-formyl-methionine and scans until the start AUG codon.
4. Large ribosomal unit is then added.
There are two sites on the ribosome P and A. An additional site E or exit site exists, but for our purposes we will discuss the P and A site. The complex is formed in the P-site.Initiation of Translation involves 4 stages:
1. Met-tRNA & GTP & initiation factor.
2. Met-tRNA added to small ribosomal subunit,
3. Small subunit binds mRNA, a reaction driven by ATP hydrolysis, attachment on the 5 of mRNA of a formyl group resulting in N-formyl-methionine and scans until the start AUG codon.
4. Large ribosomal unit is then added.
There are two sites on the ribosome P and A. An additional site E or exit site exists, but for our purposes we will discuss the P and A site. The complex is formed in the P-site.
24. Elongation Elongation:
1. A new Aminoacyl-tRNA binds to the A site
2. Peptide bond formation between the amino acid at the P site and that at the A site. This is accomplished by the enzyme peptidyl transferase.
3. Translocation: The Peptidyl-tRNA formed at the A site is transferred to P site
Peptide formation is catalyzed by peptidyl transferase.
mRNA is read from the 5 to 3 direction of the mRNAElongation:
1. A new Aminoacyl-tRNA binds to the A site
2. Peptide bond formation between the amino acid at the P site and that at the A site. This is accomplished by the enzyme peptidyl transferase.
3. Translocation: The Peptidyl-tRNA formed at the A site is transferred to P site
Peptide formation is catalyzed by peptidyl transferase.
mRNA is read from the 5 to 3 direction of the mRNA
25. Elongation Elongation:
1. A new Aminoacyl-tRNA binds to the A site
2. Peptide bond formation between the amino acid at the P site and that at the A site. This is accomplished by the enzyme peptidyl transferase.
3. Translocation: The Peptidyl-tRNA formed at the A site is transferred to P site
Peptide formation is catalyzed by peptidyl transferase.
mRNA is read from the 5 to 3 direction of the mRNAElongation:
1. A new Aminoacyl-tRNA binds to the A site
2. Peptide bond formation between the amino acid at the P site and that at the A site. This is accomplished by the enzyme peptidyl transferase.
3. Translocation: The Peptidyl-tRNA formed at the A site is transferred to P site
Peptide formation is catalyzed by peptidyl transferase.
mRNA is read from the 5 to 3 direction of the mRNA
26. Elongation 2 Elongation:
Aminoacyl-tRNA binds to the A site
Peptide bond formation
Peptidyl-tRNA formed at the A site transferred to P site.
Peptide formation is catalyzed by peptidyl transferase.
Elongation:
Aminoacyl-tRNA binds to the A site
Peptide bond formation
Peptidyl-tRNA formed at the A site transferred to P site.
Peptide formation is catalyzed by peptidyl transferase.
27. Termination Stop codon reaches at A site causing release factor to bind A site with GTP instead of aminoacyl-tRNA. Hydrolyses of the tRNA peptide bond at P site occurs. Everything comes apart including the ribosome subunitsStop codon reaches at A site causing release factor to bind A site with GTP instead of aminoacyl-tRNA. Hydrolyses of the tRNA peptide bond at P site occurs. Everything comes apart including the ribosome subunits
28. Termination Stop codon reaches at A site causing release factor to bind A site with GTP instead of aminoacyl-tRNA. Hydrolyses of the tRNA peptide bond at P site occurs. Everything comes apart including the ribosome subunitsStop codon reaches at A site causing release factor to bind A site with GTP instead of aminoacyl-tRNA. Hydrolyses of the tRNA peptide bond at P site occurs. Everything comes apart including the ribosome subunits
29. Chloramphenicol -Chloramphenicol is a neutral, stable bacteriostatic compound which reversibly binds to the 50S subunit of the bacterial ribosome. It is a Broad Spectrum aero/anaero gram + or -. It enters CNS.
Toxicity: It is rarely used except in developing countries because of toxicity which includes Gastrointestinal disturbances, disruption of normal flora, Suppression of red cell production. Aplastic anemia (1/30,000) may be irreversible and fatal. Gray baby syndrome with vomitng, hypothermia, gray color shock in infants.
Clinical resistance:plasmid-encoded enzyme chloramphenicol acetyltransferase.
-Chloramphenicol is a neutral, stable bacteriostatic compound which reversibly binds to the 50S subunit of the bacterial ribosome. It is a Broad Spectrum aero/anaero gram + or -. It enters CNS.
Toxicity: It is rarely used except in developing countries because of toxicity which includes Gastrointestinal disturbances, disruption of normal flora, Suppression of red cell production. Aplastic anemia (1/30,000) may be irreversible and fatal. Gray baby syndrome with vomitng, hypothermia, gray color shock in infants.
Clinical resistance:plasmid-encoded enzyme chloramphenicol acetyltransferase.
30. Tetracyclines Tetracyclines are also broad spectrum for gram + and -. And some protozoa. They bind the 30S ribosome subunit block the binding of aminoacyl-tRNA t the A site preventing the addition of amino acids to the growing peptide.
Workhorse: Doxycycline and tetracycline and minocycline
Clinical uses: Rickettsial diseases, chlamydiae, acne and more. Minocycline is more hydrophobic so it can reach mostly anywhere. Tet for acne.
Adverse reactions: Hypersensitvity not uncommon. Modify normal flora. Gastrointestinal. Most importantly Tet binds Calcium and therefore bones and teeth especially in children under 8 years may cause growth inhibition and yellow teeth. Can impair hepatic function. Also demeclocycline and dox may cause sun sensitivity. Some vestibular (dizziness etc) effects at high doses. Hepatic toxicity during pregnancy.
Absorption is impaired by food (except doxycycline and minocycline) and divalent cations. (Mg2+).
Doxycycline is not eliminated via the renal route and is therefore of choice in renal insufficiency.
Tetracyclines are also broad spectrum for gram + and -. And some protozoa. They bind the 30S ribosome subunit block the binding of aminoacyl-tRNA t the A site preventing the addition of amino acids to the growing peptide.
Workhorse: Doxycycline and tetracycline and minocycline
Clinical uses: Rickettsial diseases, chlamydiae, acne and more. Minocycline is more hydrophobic so it can reach mostly anywhere. Tet for acne.
Adverse reactions: Hypersensitvity not uncommon. Modify normal flora. Gastrointestinal. Most importantly Tet binds Calcium and therefore bones and teeth especially in children under 8 years may cause growth inhibition and yellow teeth. Can impair hepatic function. Also demeclocycline and dox may cause sun sensitivity. Some vestibular (dizziness etc) effects at high doses. Hepatic toxicity during pregnancy.
Absorption is impaired by food (except doxycycline and minocycline) and divalent cations. (Mg2+).
Doxycycline is not eliminated via the renal route and is therefore of choice in renal insufficiency.
31. Tetracyclines Tetracyclines are also broad spectrum for gram + and -. And some protozoa. They bind the 30S ribosome subunit block the binding of aminoacyl-tRNA t the A site preventing the addition of amino acids to the growing peptide.
Workhorse: Doxycycline and tetracycline and minocycline
Clinical uses: Rickettsial diseases, chlamydiae, acne and more. Minocycline is more hydrophobic so it can reach mostly anywhere. Tet for acne.
Adverse reactions: Hypersensitvity not uncommon. Modify normal flora. Gastrointestinal. Most importantly Tet binds Calcium and therefore bones and teeth especially in children under 8 years may cause growth inhibition and yellow teeth. Can impair hepatic function. Also demeclocycline and dox may cause sun sensitivity. Some vestibular (dizziness etc) effects at high doses. Hepatic toxicity during pregnancy.
Absorption is impaired by food (except doxycycline and minocycline) and divalent cations. (Mg2+).
Doxycycline is not eliminated via the renal route and is therefore of choice in renal insufficiency.
Tetracyclines are also broad spectrum for gram + and -. And some protozoa. They bind the 30S ribosome subunit block the binding of aminoacyl-tRNA t the A site preventing the addition of amino acids to the growing peptide.
Workhorse: Doxycycline and tetracycline and minocycline
Clinical uses: Rickettsial diseases, chlamydiae, acne and more. Minocycline is more hydrophobic so it can reach mostly anywhere. Tet for acne.
Adverse reactions: Hypersensitvity not uncommon. Modify normal flora. Gastrointestinal. Most importantly Tet binds Calcium and therefore bones and teeth especially in children under 8 years may cause growth inhibition and yellow teeth. Can impair hepatic function. Also demeclocycline and dox may cause sun sensitivity. Some vestibular (dizziness etc) effects at high doses. Hepatic toxicity during pregnancy.
Absorption is impaired by food (except doxycycline and minocycline) and divalent cations. (Mg2+).
Doxycycline is not eliminated via the renal route and is therefore of choice in renal insufficiency.
32. Tetracycline Resistance Resistance: 1. Decreased influx or increased efflux do to an active pump encoded on a plasmid and the most important resistance. 2. Protection by proteins that interfere in ribosome binding. 3. Enzymatic inactivation. Plasmids with tet resistance may carry genes for resistance to other agents such as aminoglycosides, sulfonamides, and chrlorampenicol Tet res. is therefore a marker for multiple drug resistance.
Note: Overuse of Tetracycline even in animal feed to enhance growth has cause resistance in enteric bacteria, staph, pneumococci and other bacteria.Resistance: 1. Decreased influx or increased efflux do to an active pump encoded on a plasmid and the most important resistance. 2. Protection by proteins that interfere in ribosome binding. 3. Enzymatic inactivation. Plasmids with tet resistance may carry genes for resistance to other agents such as aminoglycosides, sulfonamides, and chrlorampenicol Tet res. is therefore a marker for multiple drug resistance.
Note: Overuse of Tetracycline even in animal feed to enhance growth has cause resistance in enteric bacteria, staph, pneumococci and other bacteria.
33. Macrolides Macrolides contain a macrocyclic lactone ring (14-16 atoms) with deoxy sugars attached. They are dispensed as esters and salts. Binds the 50S rRNA and prevents aminoacyl translocation and formation of initiation complexes.
Erythromycin: Gram + expecially pneumococci, strept, staph and corynebcteria. Also Gram - like neisseria species. Bactericidal or static.
Clinical uses: corynebacterial infections (diptheria, corynebacterial sepsis, erythrasma), respiratory, neonatal, ocular or genital chlamydial infections
treatment of community acquired pneumonia because its spectrum of activity includes pneumococccus, mycoplasma and legionella
Resistance: Plasmid encoded 1. Reduced permeability or increased efflux. 2. Esterases. 3. Modification or ribsome binding site (ribosomal protection) by chromosome mutation or a methylase. Efflux and methylase predominant. Protection may also be extended to other antibiotics result in macrolide-lincosamide streptogramin or MLS-type B, resistance which share the same ribosomal binding site.
Pharmacology: Not in CNS, excreted in bile and feces.Taken up by polymorphonuclear leukocytes and macrophages and reaches the fetus.
Adverse reactions: Gasstrointestinal: gut motility, anorexia nausea, Liver:Acute cholestatic hepatitis (Allergic? fever, jaundice, impaired liver function). Inhibits cytochrome P450 increasing concentration of other drugs.Macrolides contain a macrocyclic lactone ring (14-16 atoms) with deoxy sugars attached. They are dispensed as esters and salts. Binds the 50S rRNA and prevents aminoacyl translocation and formation of initiation complexes.
Erythromycin: Gram + expecially pneumococci, strept, staph and corynebcteria. Also Gram - like neisseria species. Bactericidal or static.
Clinical uses: corynebacterial infections (diptheria, corynebacterial sepsis, erythrasma), respiratory, neonatal, ocular or genital chlamydial infections
treatment of community acquired pneumonia because its spectrum of activity includes pneumococccus, mycoplasma and legionella
Resistance: Plasmid encoded 1. Reduced permeability or increased efflux. 2. Esterases. 3. Modification or ribsome binding site (ribosomal protection) by chromosome mutation or a methylase. Efflux and methylase predominant. Protection may also be extended to other antibiotics result in macrolide-lincosamide streptogramin or MLS-type B, resistance which share the same ribosomal binding site.
Pharmacology: Not in CNS, excreted in bile and feces.Taken up by polymorphonuclear leukocytes and macrophages and reaches the fetus.
Adverse reactions: Gasstrointestinal: gut motility, anorexia nausea, Liver:Acute cholestatic hepatitis (Allergic? fever, jaundice, impaired liver function). Inhibits cytochrome P450 increasing concentration of other drugs.
34. Macrolides Macrolides contain a macrocyclic lactone ring (14-16 atoms) with deoxy sugars attached. They are dispensed as esters and salts. Binds the 50S rRNA and prevents aminoacyl translocation and formation of initiation complexes.
Erythromycin: Gram + expecially pneumococci, strept, staph and corynebcteria. Also Gram - like neisseria species. Bactericidal or static.
Clinical uses: corynebacterial infections (diptheria, corynebacterial sepsis, erythrasma), respiratory, neonatal, ocular or genital chlamydial infections
treatment of community acquired pneumonia because its spectrum of activity includes pneumococccus, mycoplasma and legionella
Resistance: Plasmid encoded 1. Reduced permeability or increased efflux. 2. Esterases. 3. Modification or ribsome binding site (ribosomal protection) by chromosome mutation or a methylase. Efflux and methylase predominant. Protection may also be extended to other antibiotics result in macrolide-lincosamide streptogramin or MLS-type B, resistance which share the same ribosomal binding site.
Pharmacology: Not in CNS, excreted in bile and feces.Taken up by polymorphonuclear leukocytes and macrophages and reaches the fetus.
Adverse reactions: Gasstrointestinal: gut motility, anorexia nausea, Liver:Acute cholestatic hepatitis (Allergic? fever, jaundice, impaired liver function). Inhibits cytochrome P450 increasing concentration of other drugs.Macrolides contain a macrocyclic lactone ring (14-16 atoms) with deoxy sugars attached. They are dispensed as esters and salts. Binds the 50S rRNA and prevents aminoacyl translocation and formation of initiation complexes.
Erythromycin: Gram + expecially pneumococci, strept, staph and corynebcteria. Also Gram - like neisseria species. Bactericidal or static.
Clinical uses: corynebacterial infections (diptheria, corynebacterial sepsis, erythrasma), respiratory, neonatal, ocular or genital chlamydial infections
treatment of community acquired pneumonia because its spectrum of activity includes pneumococccus, mycoplasma and legionella
Resistance: Plasmid encoded 1. Reduced permeability or increased efflux. 2. Esterases. 3. Modification or ribsome binding site (ribosomal protection) by chromosome mutation or a methylase. Efflux and methylase predominant. Protection may also be extended to other antibiotics result in macrolide-lincosamide streptogramin or MLS-type B, resistance which share the same ribosomal binding site.
Pharmacology: Not in CNS, excreted in bile and feces.Taken up by polymorphonuclear leukocytes and macrophages and reaches the fetus.
Adverse reactions: Gasstrointestinal: gut motility, anorexia nausea, Liver:Acute cholestatic hepatitis (Allergic? fever, jaundice, impaired liver function). Inhibits cytochrome P450 increasing concentration of other drugs.
35. Macrolides Macrolides contain a macrocyclic lactone ring (14-16 atoms) with deoxy sugars attached. They are dispensed as esters and salts. Binds the 50S rRNA and prevents aminoacyl translocation and formation of initiation complexes.
Erythromycin: Gram + expecially pneumococci, strept, staph and corynebcteria. Also Gram - like neisseria species. Bactericidal or static.
Clinical uses: corynebacterial infections (diptheria, corynebacterial sepsis, erythrasma), respiratory, neonatal, ocular or genital chlamydial infections
treatment of community acquired pneumonia because its spectrum of activity includes pneumococccus, mycoplasma and legionella
Resistance: Plasmid encoded 1. Reduced permeability or increased efflux. 2. Esterases. 3. Modification or ribsome binding site (ribosomal protection) by chromosome mutation or a methylase. Efflux and methylase predominant. Protection may also be extended to other antibiotics result in macrolide-lincosamide streptogramin or MLS-type B, resistance which share the same ribosomal binding site.
Pharmacology: Not in CNS, excreted in bile and feces.Taken up by polymorphonuclear leukocytes and macrophages and reaches the fetus.
Adverse reactions: Gasstrointestinal: gut motility, anorexia nausea, Liver:Acute cholestatic hepatitis (Allergic? fever, jaundice, impaired liver function). Inhibits cytochrome P450 increasing concentration of other drugs.Macrolides contain a macrocyclic lactone ring (14-16 atoms) with deoxy sugars attached. They are dispensed as esters and salts. Binds the 50S rRNA and prevents aminoacyl translocation and formation of initiation complexes.
Erythromycin: Gram + expecially pneumococci, strept, staph and corynebcteria. Also Gram - like neisseria species. Bactericidal or static.
Clinical uses: corynebacterial infections (diptheria, corynebacterial sepsis, erythrasma), respiratory, neonatal, ocular or genital chlamydial infections
treatment of community acquired pneumonia because its spectrum of activity includes pneumococccus, mycoplasma and legionella
Resistance: Plasmid encoded 1. Reduced permeability or increased efflux. 2. Esterases. 3. Modification or ribsome binding site (ribosomal protection) by chromosome mutation or a methylase. Efflux and methylase predominant. Protection may also be extended to other antibiotics result in macrolide-lincosamide streptogramin or MLS-type B, resistance which share the same ribosomal binding site.
Pharmacology: Not in CNS, excreted in bile and feces.Taken up by polymorphonuclear leukocytes and macrophages and reaches the fetus.
Adverse reactions: Gasstrointestinal: gut motility, anorexia nausea, Liver:Acute cholestatic hepatitis (Allergic? fever, jaundice, impaired liver function). Inhibits cytochrome P450 increasing concentration of other drugs.
36. Macrolides 2 Clarithromycin
is derived from erythromycin by addition of a methyl group improving acid stability and absorption. It is for most purposes similar to Erythromycin regarding antibacterial activity and resistance (more active though against Mycobaterium avium)
Advantage: lower frequency of gastrointestinal intolerance and less frequent dosing. Choice depends on pricing and tolerability.
Azithromycin
Has an additional methylated nitrogen in the l5 atom lactone ring. It has a long half life.
Advantage: pharmacological. It enters tisuues well and is slowly released resulting in a 3 day half life. 1 day dosing is as effective as a 7-day doxycycline treatment for urethritis. A short course of therapy, 5 days is therefore possible for community acquired pneumonia. Also does not inactivate cytochrome P450.
Ketolides
Semisynthetic substituion is of a 3-keto group for the neutral sugar L-cladinose. These I believe are currently not available but will be shortly.
Clarithromycin
is derived from erythromycin by addition of a methyl group improving acid stability and absorption. It is for most purposes similar to Erythromycin regarding antibacterial activity and resistance (more active though against Mycobaterium avium)
Advantage: lower frequency of gastrointestinal intolerance and less frequent dosing. Choice depends on pricing and tolerability.
Azithromycin
Has an additional methylated nitrogen in the l5 atom lactone ring. It has a long half life.
Advantage: pharmacological. It enters tisuues well and is slowly released resulting in a 3 day half life. 1 day dosing is as effective as a 7-day doxycycline treatment for urethritis. A short course of therapy, 5 days is therefore possible for community acquired pneumonia. Also does not inactivate cytochrome P450.
Ketolides
Semisynthetic substituion is of a 3-keto group for the neutral sugar L-cladinose. These I believe are currently not available but will be shortly.
37. Macrolides 2 Clarithromycin
is derived from erythromycin by addition of a methyl group improving acid stability and absorption. It is for most purposes similar to Erythromycin regarding antibacterial activity and resistance (more active though against Mycobaterium avium)
Advantage: lower frequency of gastrointestinal intolerance and less frequent dosing. Choice depends on pricing and tolerability.
Azithromycin
Has an additional methylated nitrogen in the l5 atom lactone ring. It has a long half life.
Advantage: pharmacological. It enters tisuues well and is slowly released resulting in a 3 day half life. 1 day dosing is as effective as a 7-day doxycycline treatment for urethritis. A short course of therapy, 5 days is therefore possible for community acquired pneumonia. Also does not inactivate cytochrome P450.
Ketolides
Semisynthetic substituion is of a 3-keto group for the neutral sugar L-cladinose. These I believe are currently not available but will be shortly.
Clarithromycin
is derived from erythromycin by addition of a methyl group improving acid stability and absorption. It is for most purposes similar to Erythromycin regarding antibacterial activity and resistance (more active though against Mycobaterium avium)
Advantage: lower frequency of gastrointestinal intolerance and less frequent dosing. Choice depends on pricing and tolerability.
Azithromycin
Has an additional methylated nitrogen in the l5 atom lactone ring. It has a long half life.
Advantage: pharmacological. It enters tisuues well and is slowly released resulting in a 3 day half life. 1 day dosing is as effective as a 7-day doxycycline treatment for urethritis. A short course of therapy, 5 days is therefore possible for community acquired pneumonia. Also does not inactivate cytochrome P450.
Ketolides
Semisynthetic substituion is of a 3-keto group for the neutral sugar L-cladinose. These I believe are currently not available but will be shortly.
38. Clindamycin Clindamycin is derived from lincomycin which is toxic and not used. It resembles erthromycin in activity and also binds the the same site on the 50S ribosomal subunit interfering with the formation of initiation complexes and with aminoacyl translocation.
Antibacterial Activity: Used for gram + anaerobic head and neck infections. staph and strep. Mostly for severe anaerobic infection by bacteriodes. Also used as prophylaxis of endocarditis in patients with valvular heart disease undergoing dental procedures. Used for penetrating wounds of the abdomen or gut, infections in female genital tract.
Resistant bacteria: Clostridium difficile causes pseudomembranous colitis, Enterococci and gram negative aerobic organisms are resistant.
Adverse Effects: Gastrointestinal, skin rashes, Impaired liver function. Potentially fatal antibiotic associated Colitis caused by toxigenic C difficile has been noticed which can be treated by metronidazole or vancomycin.
Clindamycin is derived from lincomycin which is toxic and not used. It resembles erthromycin in activity and also binds the the same site on the 50S ribosomal subunit interfering with the formation of initiation complexes and with aminoacyl translocation.
Antibacterial Activity: Used for gram + anaerobic head and neck infections. staph and strep. Mostly for severe anaerobic infection by bacteriodes. Also used as prophylaxis of endocarditis in patients with valvular heart disease undergoing dental procedures. Used for penetrating wounds of the abdomen or gut, infections in female genital tract.
Resistant bacteria: Clostridium difficile causes pseudomembranous colitis, Enterococci and gram negative aerobic organisms are resistant.
Adverse Effects: Gastrointestinal, skin rashes, Impaired liver function. Potentially fatal antibiotic associated Colitis caused by toxigenic C difficile has been noticed which can be treated by metronidazole or vancomycin.
39. Clindamycin Clindamycin is derived from lincomycin which is toxic and not used. It resembles erthromycin in activity and also binds the the same site on the 50S ribosomal subunit interfering with the formation of initiation complexes and with aminoacyl translocation.
Antibacterial Activity: Used for gram + anaerobic head and neck infections. staph and strep. Mostly for severe anaerobic infection by bacteriodes. Also used as prophylaxis of endocarditis in patients with valvular heart disease undergoing dental procedures. Used for penetrating wounds of the abdomen or gut, infections in female genital tract.
Resistant bacteria: Clostridium difficile causes pseudomembranous colitis, Enterococci and gram negative aerobic organisms are resistant.
Adverse Effects: Gastrointestinal, skin rashes, Impaired liver function. Potentially fatal antibiotic associated Colitis caused by toxigenic C difficile has been noticed which can be treated by metronidazole or vancomycin.
Clindamycin is derived from lincomycin which is toxic and not used. It resembles erthromycin in activity and also binds the the same site on the 50S ribosomal subunit interfering with the formation of initiation complexes and with aminoacyl translocation.
Antibacterial Activity: Used for gram + anaerobic head and neck infections. staph and strep. Mostly for severe anaerobic infection by bacteriodes. Also used as prophylaxis of endocarditis in patients with valvular heart disease undergoing dental procedures. Used for penetrating wounds of the abdomen or gut, infections in female genital tract.
Resistant bacteria: Clostridium difficile causes pseudomembranous colitis, Enterococci and gram negative aerobic organisms are resistant.
Adverse Effects: Gastrointestinal, skin rashes, Impaired liver function. Potentially fatal antibiotic associated Colitis caused by toxigenic C difficile has been noticed which can be treated by metronidazole or vancomycin.
40. Streptogramins (Quinupristin-dalfopristin) and Oxazoladinones (Linezolid) These new agents are a blessing.
Streptogramins
Quinupristin-dalfopristin is a intravenously administered mixture which is rapidly bactericidal for most organisms except Enterococcus faecium which is killed slowly.
It is acitve against gram + cocci including drug-resistant strains of strep and staph.
Resistance: modification of the quinupristin binding site, enzymatic inactivation of dalfopristin or efflux.
Oxazoladinones
A new class of synthetic antimicrobials. Active against gram + including staph, strp, enterococci, rods such as corynebacteria.
Binds to the 23S rRNA of the 50S subunit, preventing the formation of the ribosome complex. NO KNOWN CROSS RESISTANCE WITH OTHER drug classes.
Aproved only for vancomycin-resistant E faecium (VRE) and infections caused by multiple-drug resistant organisms.These new agents are a blessing.
Streptogramins
Quinupristin-dalfopristin is a intravenously administered mixture which is rapidly bactericidal for most organisms except Enterococcus faecium which is killed slowly.
It is acitve against gram + cocci including drug-resistant strains of strep and staph.
Resistance: modification of the quinupristin binding site, enzymatic inactivation of dalfopristin or efflux.
Oxazoladinones
A new class of synthetic antimicrobials. Active against gram + including staph, strp, enterococci, rods such as corynebacteria.
Binds to the 23S rRNA of the 50S subunit, preventing the formation of the ribosome complex. NO KNOWN CROSS RESISTANCE WITH OTHER drug classes.
Aproved only for vancomycin-resistant E faecium (VRE) and infections caused by multiple-drug resistant organisms.
41. Streptogramins and Oxazoladinones These new agents are a blessing.
Streptogramins
Quinupristin-dalfopristin is a intravenously administered mixture which is rapidly bactericidal for most organisms except Enterococcus faecium which is killed slowly.
It is acitve against gram + cocci including drug-resistant strains of strep and staph.
Resistance: modification of the quinupristin binding site, enzymatic inactivation of dalfopristin or efflux.
Oxazoladinones
A new class of synthetic antimicrobials. Active against gram + including staph, strp, enterococci, rods such as corynebacteria.
Binds to the 23S rRNA of the 50S subunit, preventing the formation of the ribosome complex. NO KNOWN CROSS RESISTANCE WITH OTHER drug classes.
Aproved only for vancomycin-resistant E faecium (VRE) and infections caused by multiple-drug resistant organisms.These new agents are a blessing.
Streptogramins
Quinupristin-dalfopristin is a intravenously administered mixture which is rapidly bactericidal for most organisms except Enterococcus faecium which is killed slowly.
It is acitve against gram + cocci including drug-resistant strains of strep and staph.
Resistance: modification of the quinupristin binding site, enzymatic inactivation of dalfopristin or efflux.
Oxazoladinones
A new class of synthetic antimicrobials. Active against gram + including staph, strp, enterococci, rods such as corynebacteria.
Binds to the 23S rRNA of the 50S subunit, preventing the formation of the ribosome complex. NO KNOWN CROSS RESISTANCE WITH OTHER drug classes.
Aproved only for vancomycin-resistant E faecium (VRE) and infections caused by multiple-drug resistant organisms.
42. Aminoglycosides Aminoglycosides contain a hexose ring, streptidine in streptomysin with other amino sugars attached by gylcosidic linkages. They act synergistically with B-lactams or vancomycin though can complex together at high concentrations so are not administered together.
Mechanims of action: Drug diffuses via porin and actively transported to cytoplasm via an oxygen dependant process. The electrochemical gradient supplies the energy is coupled to a proton pump. Low extracellar pH or anaerobic conditioons inhibit the transport.
Transport can be enhanced by cell wall drugs, the basis of synergism.
They bind the 30S ribosomal proteins (S12 for streptomycin). Inhibition is by : 1. Interference with initiation 2. Induction of misreading of mRNA 3. Causes a breakup of polysomes into nonfunctional monosomes.
Resistance: 1. The primary cause is : Transferase enzyme inactivate the aminoglycosie by adenylylation, acetylation or phosphorylation. 2. Also impaired entry into cell, via deletion of a porin protein or affects on the transport system 3. The target protein is deleted or altered by mutation.Aminoglycosides contain a hexose ring, streptidine in streptomysin with other amino sugars attached by gylcosidic linkages. They act synergistically with B-lactams or vancomycin though can complex together at high concentrations so are not administered together.
Mechanims of action: Drug diffuses via porin and actively transported to cytoplasm via an oxygen dependant process. The electrochemical gradient supplies the energy is coupled to a proton pump. Low extracellar pH or anaerobic conditioons inhibit the transport.
Transport can be enhanced by cell wall drugs, the basis of synergism.
They bind the 30S ribosomal proteins (S12 for streptomycin). Inhibition is by : 1. Interference with initiation 2. Induction of misreading of mRNA 3. Causes a breakup of polysomes into nonfunctional monosomes.
Resistance: 1. The primary cause is : Transferase enzyme inactivate the aminoglycosie by adenylylation, acetylation or phosphorylation. 2. Also impaired entry into cell, via deletion of a porin protein or affects on the transport system 3. The target protein is deleted or altered by mutation.
43. Aminoglycosides Aminoglycosides contain a hexose ring, streptidine in streptomysin with other amino sugars attached by gylcosidic linkages. They act synergistically with B-lactams or vancomycin though can complex together at high concentrations so are not administered together.
Mechanims of action: Drug diffuses via porin and actively transported to cytoplasm via an oxygen dependant process. The electrochemical gradient supplies the energy is coupled to a proton pump. Low extracellar pH or anaerobic conditioons inhibit the transport.
Transport can be enhanced by cell wall drugs, the basis of synergism.
They bind the 30S ribosomal proteins (S12 for streptomycin). Inhibition is by : 1. Interference with initiation 2. Induction of misreading of mRNA 3. Causes a breakup of polysomes into nonfunctional monosomes.
Resistance: 1. The primary cause is : Transferase enzyme inactivate the aminoglycosie by adenylylation, acetylation or phosphorylation. 2. Also impaired entry into cell, via deletion of a porin protein or affects on the transport system 3. The target protein is deleted or altered by mutation.Aminoglycosides contain a hexose ring, streptidine in streptomysin with other amino sugars attached by gylcosidic linkages. They act synergistically with B-lactams or vancomycin though can complex together at high concentrations so are not administered together.
Mechanims of action: Drug diffuses via porin and actively transported to cytoplasm via an oxygen dependant process. The electrochemical gradient supplies the energy is coupled to a proton pump. Low extracellar pH or anaerobic conditioons inhibit the transport.
Transport can be enhanced by cell wall drugs, the basis of synergism.
They bind the 30S ribosomal proteins (S12 for streptomycin). Inhibition is by : 1. Interference with initiation 2. Induction of misreading of mRNA 3. Causes a breakup of polysomes into nonfunctional monosomes.
Resistance: 1. The primary cause is : Transferase enzyme inactivate the aminoglycosie by adenylylation, acetylation or phosphorylation. 2. Also impaired entry into cell, via deletion of a porin protein or affects on the transport system 3. The target protein is deleted or altered by mutation.
44. Aminoglycosides Aminoglycosides contain a hexose ring, streptidine in streptomysin with other amino sugars attached by gylcosidic linkages. They act synergistically with B-lactams or vancomycin though can complex together at high concentrations so are not administered together.
Mechanims of action: Drug diffuses via porin and actively transported to cytoplasm via an oxygen dependant process. The electrochemical gradient supplies the energy is coupled to a proton pump. Low extracellar pH or anaerobic conditioons inhibit the transport.
Transport can be enhanced by cell wall drugs, the basis of synergism.
They bind the 30S ribosomal proteins (S12 for streptomycin). Inhibition is by : 1. Interference with initiation 2. Induction of misreading of mRNA 3. Causes a breakup of polysomes into nonfunctional monosomes.
Resistance: 1. The primary cause is : Transferase enzyme inactivate the aminoglycosie by adenylylation, acetylation or phosphorylation. 2. Also impaired entry into cell, via deletion of a porin protein or affects on the transport system 3. The target protein is deleted or altered by mutation.Aminoglycosides contain a hexose ring, streptidine in streptomysin with other amino sugars attached by gylcosidic linkages. They act synergistically with B-lactams or vancomycin though can complex together at high concentrations so are not administered together.
Mechanims of action: Drug diffuses via porin and actively transported to cytoplasm via an oxygen dependant process. The electrochemical gradient supplies the energy is coupled to a proton pump. Low extracellar pH or anaerobic conditioons inhibit the transport.
Transport can be enhanced by cell wall drugs, the basis of synergism.
They bind the 30S ribosomal proteins (S12 for streptomycin). Inhibition is by : 1. Interference with initiation 2. Induction of misreading of mRNA 3. Causes a breakup of polysomes into nonfunctional monosomes.
Resistance: 1. The primary cause is : Transferase enzyme inactivate the aminoglycosie by adenylylation, acetylation or phosphorylation. 2. Also impaired entry into cell, via deletion of a porin protein or affects on the transport system 3. The target protein is deleted or altered by mutation.
45. Aminoglycosides and drug action Aminoglycosides Inhibit translation at three distinct stages as depicted in this image.Aminoglycosides Inhibit translation at three distinct stages as depicted in this image.
46. Aminoglycosides 2 Clinical uses: No activity against anaerobes. Used most widely against gram-negative enteric bacteria in combination with vancomycin or a penecillin for endocarditis. Used especially when isolates are drug-resistant and there is a suspicion of sepsis.
They are poorly absorbed from the intact gastrointestinal tract and totally excreted. They, do not enter cells, cleared by the kidney and excretion is directly proportionate to creatinine clearance and should be based on it.
Adverse effects: Ototoxicity auditory damage high frequency hearing loss or vertigoand nephrotoxicity. In high doses can produce a curare-like effect with neuromuscular blockade and respiratory paralysis, reversible by calcium gluconate or neostigmine.
Aminoglycosides have a concentration-dependant killing as opposed to the time-dependent killing of beta-lactams. They also have a postantibiotic effect. Since toxicity is both time and concentration dependant a once a day dose is effective and can reduce toxicity.
Clinical uses: No activity against anaerobes. Used most widely against gram-negative enteric bacteria in combination with vancomycin or a penecillin for endocarditis. Used especially when isolates are drug-resistant and there is a suspicion of sepsis.
They are poorly absorbed from the intact gastrointestinal tract and totally excreted. They, do not enter cells, cleared by the kidney and excretion is directly proportionate to creatinine clearance and should be based on it.
Adverse effects: Ototoxicity auditory damage high frequency hearing loss or vertigoand nephrotoxicity. In high doses can produce a curare-like effect with neuromuscular blockade and respiratory paralysis, reversible by calcium gluconate or neostigmine.
Aminoglycosides have a concentration-dependant killing as opposed to the time-dependent killing of beta-lactams. They also have a postantibiotic effect. Since toxicity is both time and concentration dependant a once a day dose is effective and can reduce toxicity.
47. Aminoglycosides 3 Clinical uses: No activity against anaerobes. Used most widely against gram-negative enteric bacteria in combination with vancomycin or a penecillin for endocarditis. Used especially when isolates are drug-resistant and there is a suspicion of sepsis.
They are poorly absorbed from the intact gastrointestinal tract and totally excreted. They, do not enter cells, cleared by the kidney and excretion is directly proportionate to creatinine clearance and should be based on it.
Adverse effects: Ototoxicity auditory damage high frequency hearing loss or vertigoand nephrotoxicity. In high doses can produce a curare-like effect with neuromuscular blockade and respiratory paralysis, reversible by calcium gluconate or neostigmine.
Aminoglycosides have a concentration-dependant killing as opposed to the time-dependent killing of beta-lactams. They also have a postantibiotic effect. Since toxicity is both time and concentration dependant a once a day dose is effective and can reduce toxicity.
Clinical uses: No activity against anaerobes. Used most widely against gram-negative enteric bacteria in combination with vancomycin or a penecillin for endocarditis. Used especially when isolates are drug-resistant and there is a suspicion of sepsis.
They are poorly absorbed from the intact gastrointestinal tract and totally excreted. They, do not enter cells, cleared by the kidney and excretion is directly proportionate to creatinine clearance and should be based on it.
Adverse effects: Ototoxicity auditory damage high frequency hearing loss or vertigoand nephrotoxicity. In high doses can produce a curare-like effect with neuromuscular blockade and respiratory paralysis, reversible by calcium gluconate or neostigmine.
Aminoglycosides have a concentration-dependant killing as opposed to the time-dependent killing of beta-lactams. They also have a postantibiotic effect. Since toxicity is both time and concentration dependant a once a day dose is effective and can reduce toxicity.
48. Aminoglycosides can cause nephrotoxicity Nephrotoxicity occurs because of binding of the aminoglycosides (AG) to tubular cells followed by internalization into AG filled lysosomes which eventually disrupt the brush border causing leakage.
Dosages for patients with renal insufficiency need to be adjusted. A general rule is to divide the AG dosage mg/d by the serum creatinine mg/dL since AG clearance is directly proportional to creatinine clearance. A better method is to etimate creatinine clearance using the Cockcroft-Gault formula, or not use AG at all.
Nephrotoxicity tends to be reversible.Nephrotoxicity occurs because of binding of the aminoglycosides (AG) to tubular cells followed by internalization into AG filled lysosomes which eventually disrupt the brush border causing leakage.
Dosages for patients with renal insufficiency need to be adjusted. A general rule is to divide the AG dosage mg/d by the serum creatinine mg/dL since AG clearance is directly proportional to creatinine clearance. A better method is to etimate creatinine clearance using the Cockcroft-Gault formula, or not use AG at all.
Nephrotoxicity tends to be reversible.
49. Or Ototoxicity The Cochlea is lined with hair cells essential for hearing. They are destroyed by high concentrations of AG in the high frequency outer loop first and eventually in the lower loop (3rd turn), red in the above image.
Even if a patient can hear the medical provider it does not mean that there is no toxicity since the higher frequencies are first targeted.
Ototoxicity tends to be irreversible. In most cases vestibular dysfunction, sometimes loss of hearing.The Cochlea is lined with hair cells essential for hearing. They are destroyed by high concentrations of AG in the high frequency outer loop first and eventually in the lower loop (3rd turn), red in the above image.
Even if a patient can hear the medical provider it does not mean that there is no toxicity since the higher frequencies are first targeted.
Ototoxicity tends to be irreversible. In most cases vestibular dysfunction, sometimes loss of hearing.
50. Many Aminoglycosides Gentamicin, tobramycin and amikacin are most widely employed. Neomycin and kanamycin are limited to topical or oral use.
Streptomycin: not so useful because of rapidly developing resistance.Used for second-line agent for TB. Also used in plague.
Gentamycin: Effective against gram + and - bacteria. Useful for staph and coliforms and other gram-negative bacteria. Used for burns as well. Enteroccocal resistance by modifying enzymes exists across AG use but amikacin is much more resistant to it.
Tobramycin: Similar to Gentamycin.
Amikacin: Semi-synthetic more resistant to enzymes than Gent and Tobramycin.Useful for gram - enteric bacteria and some multidrug-resistant TB strains.
Kanamycin and Neomycin: Good for gram +/- and some mycobacteria. Because of toxicity use limited to oral and topical. Gentamicin, tobramycin and amikacin are most widely employed. Neomycin and kanamycin are limited to topical or oral use.
Streptomycin: not so useful because of rapidly developing resistance.Used for second-line agent for TB. Also used in plague.
Gentamycin: Effective against gram + and - bacteria. Useful for staph and coliforms and other gram-negative bacteria. Used for burns as well. Enteroccocal resistance by modifying enzymes exists across AG use but amikacin is much more resistant to it.
Tobramycin: Similar to Gentamycin.
Amikacin: Semi-synthetic more resistant to enzymes than Gent and Tobramycin.Useful for gram - enteric bacteria and some multidrug-resistant TB strains.
Kanamycin and Neomycin: Good for gram +/- and some mycobacteria. Because of toxicity use limited to oral and topical.
51. Many Aminoglycosides Gentamicin, tobramycin and amikacin are most widely employed. Neomycin and kanamycin are limited to topical or oral use.
Streptomycin: not so useful because of rapidly developing resistance.Used for second-line agent for TB. Also used in plague.
Gentamycin: Effective against gram + and - bacteria. Useful for staph and coliforms and other gram-negative bacteria. Used for burns as well. Enteroccocal resistance by modifying enzymes exists across AG use but amikacin is much more resistant to it.
Tobramycin: Similar to Gentamycin.
Amikacin: Semi-synthetic more resistant to enzymes than Gent and Tobramycin.Useful for gram - enteric bacteria and some multidrug-resistant TB strains.
Kanamycin and Neomycin: Good for gram +/- and some mycobacteria. Because of toxicity use limited to oral and topical. Gentamicin, tobramycin and amikacin are most widely employed. Neomycin and kanamycin are limited to topical or oral use.
Streptomycin: not so useful because of rapidly developing resistance.Used for second-line agent for TB. Also used in plague.
Gentamycin: Effective against gram + and - bacteria. Useful for staph and coliforms and other gram-negative bacteria. Used for burns as well. Enteroccocal resistance by modifying enzymes exists across AG use but amikacin is much more resistant to it.
Tobramycin: Similar to Gentamycin.
Amikacin: Semi-synthetic more resistant to enzymes than Gent and Tobramycin.Useful for gram - enteric bacteria and some multidrug-resistant TB strains.
Kanamycin and Neomycin: Good for gram +/- and some mycobacteria. Because of toxicity use limited to oral and topical.
52. Mupirocin (pseudomonic acid, bactroban)
53. Mechanism of inhibition of translation
54. Binding sites and bactericidal or Bacteriostatic
55. Metronidazole Another mechanism for antibiotic development is transcription in that RNA polymerase, which generates all the cellular mRNA is inhibited.
Rifampin a TB drug, inhibits bacterial RNA polymerase but not of eukaryotes. Although both pro and eukaryote polymerases have a similar structure as we can see in the image, the rifampin binding pocket is different leading to specificity.
There will be a lecture on TB so will stop here.Another mechanism for antibiotic development is transcription in that RNA polymerase, which generates all the cellular mRNA is inhibited.
Rifampin a TB drug, inhibits bacterial RNA polymerase but not of eukaryotes. Although both pro and eukaryote polymerases have a similar structure as we can see in the image, the rifampin binding pocket is different leading to specificity.
There will be a lecture on TB so will stop here.
56. Summary Material Know the major mechanisms of actions of the antibiotic. It should be relatively easy to read the material in Basic and Clinical Pharmacology of Katzung.
Below are items that require reviewing.Know the major mechanisms of actions of the antibiotic. It should be relatively easy to read the material in Basic and Clinical Pharmacology of Katzung.
Below are items that require reviewing.
