antibiotics lecture 04
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Bio 319: Antibiotics
Lecture Four
TopicInhibitors of Nucleic acid synthesisInhibitors of synthesis of essential metabolitesIntroduction to antibiotics resistance
Lecturer: Dr. G. Kattam Maiyoh
03/21/13 GKM/BIO319:Antibiotics/Sem2/2013 1
Reminder
03/21/13 2GKM/BIO319:Antibiotics/Sem2/2013
The Action of Antimicrobial Drugs
03/21/13 3GKM/BIO319:Antibiotics/Sem2/2013
Inhibitors of Cell Wall Synthesis
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Protein synthesis inhibitors– Aminoglycosides
– Tetracyclins
- Spectinomycin
– Macrolides
– Chloramphenicol
– Clindamycin
03/21/13 GKM/BIO319:Antibiotics/Sem2/2013 5
Inhibitors of Nucleic Acid Synthesis
~Inhibitors of DNA synthesis~Inhibitors of RNA synthesis
03/21/13 6GKM/BIO319:Antibiotics/Sem2/2013
Inhibitors of RNA SynthesisFor this class of antibiotics, selectivity is due to differences between prokaryotic and eukaryotic RNA polymerase i.e.
All RNA polymerases are multi-protein complexes, however, the number of proteins that are assembled to form the active enzyme is much larger in eukaryotes;
•The basic catalytic core is made up of 12 subunits.
•By comparison, bacterial RNAP has 5 subunits.
03/21/13 7GKM/BIO319:Antibiotics/Sem2/2013
Rifampin, Rifamycin, Rifampicin, Rifabutin (bactericidal)
• Mode of action - These antimicrobials bind to DNA-dependent RNA polymerase and inhibit initiation of mRNA synthesis.
• Spectrum of activity - Broad spectrum but is used most commonly in the treatment of tuberculosis
• Resistance – Common– For example; – Resistance to rifampicin develops quickly during treatment, so
monotherapy should not be used to treat these infections — it should be used in combination with other antibiotics.
– Resistance to rifampicin arises from mutations that alter residues of the rifampicin binding site on RNA polymerase, resulting in decreased affinity for rifampicin.
• Combination therapy - Since resistance is common, rifampin is usually used in combination therapy.
03/21/13 8GKM/BIO319:Antibiotics/Sem2/2013
Inhibitors of DNA SynthesisFor this class of antibiotics, selectivity due to differences between prokaryotic and eukaryotic DNA replication enzymes
Consider the following:
Eukaryotic replication is more complicated. •First, they have multiple ori per chromosome that allow for bidirectional synthesis of the linear chromosome. •They also use several DNA polymerases (I, II, III), and ligase (seals the nicks in the DNA strand), and RNA primer (gives a 3' end for the DNA polymerase to start synthesis).
•As for other differences in their synthesis of DNA is their speed, prokaryotes can replicate their chromosome at about 1,000 bp/sec, while eukaryotes can replicate their chromosomes at about 100 bp/sec. •They also differ in the number of ori, eukaryotes (as it was stated above) has multiple ori, while prokaryotes have only one.
03/21/13 9GKM/BIO319:Antibiotics/Sem2/2013
The Quinolones
• Current drugs are fluoridated 4-quinolones
• Broad coverage (some broader than others)
• Targets DNA gyrase (G-) and topoisomerase IV (G+)
• Resistance due to efflux and mutations in targets
03/21/13 10GKM/BIO319:Antibiotics/Sem2/2013
Pharmacological attributes of Quinolones• Favorable pharmacological attributes
– Orally administered, quickly absorbed, even with a full stomach
– Excellent bioavailability in a wide range of tissues and body fluids (including inside cells)
• Mostly cleared by the kidneys– Exceptions are pefloxacin and
moxifloxacin which are metabolized by liver
• Ciprofloxacin, ofloxacin, and pefloxacin are excreted in breast milk
““Got Cipro?”Got Cipro?”
03/21/13 11GKM/BIO319:Antibiotics/Sem2/2013
Therapeutic Uses of Quinolones
• Urinary tract infections
• Prostatitis• STD’s– Chlamydia– Chancroid - painful
sores on the genitalia– Not syphilis or
gonorrhea (due to increased resistance)
03/21/13 12GKM/BIO319:Antibiotics/Sem2/2013
Therapeutic Uses of Quinolones
• GI and abdominal – Travelers diarrhea– Shigellosis– Typhoid fever
• Respiratory tract– New agents for strep. pneumonia
03/21/13 13GKM/BIO319:Antibiotics/Sem2/2013
Therapeutic Uses of Quinolones
• Bone, joint, soft tissue– Ideal for chronic
osteomylitis - infection of the bone or bone marrow• Resistance developing in
S. aureus, P. aeruginosa, and S. marcesens
– Good against polymicrobial infections like diabetic foot ulcers
03/21/13 14GKM/BIO319:Antibiotics/Sem2/2013
Therapeutic Uses of Quinolones
• Ciprofloxacin for anthrax and tuleremia (rabbit fever, deer fly fever, Ohara's fever)
• Combined with other drugs, useful for atypical Mycobacterium sp.
Pulmonary AnthraxPulmonary Anthrax
03/21/13 15GKM/BIO319:Antibiotics/Sem2/2013
Toxicity/Contraindications of Quinolones• Nausea, vomiting, abdominal discomfort (common)• Diarrhea and antibiotic-associated colitis (uncommon to rare)• CNS side effects
– Mild headache and dizziness (common to rare)– Hallucinations, delirium, and seizures (rare)
• Arthropy in immature animals (common)– Quinolones not given to children unless benefits outweigh the risks
• Leukopenia, eosinophila, heart arythmias (rare)
delirium - disorder involving incoherent speech, hallucinations, etc., caused by intoxication, fever, etc
03/21/13 16GKM/BIO319:Antibiotics/Sem2/2013
Antimetabolite Antimicrobials
03/21/13 17GKM/BIO319:Antibiotics/Sem2/2013
Inhibitors of Folic Acid Synthesis
• Basis of Selectivity• Review of Folic
Acid Metabolism
p-aminobenzoic acid + Pteridine
Dihydropteroic acid
Dihydrofolic acid
Tetrahydrofolic acid
Pteridine synthetase
Dihydrofolate synthetase
Dihydrofolate reductase
ThymidinePurines
Methionine
Trimethoprim
Sulfonamides
03/21/13 18GKM/BIO319:Antibiotics/Sem2/2013
Sulfonamides, Sulfones (bacteriostatic)
• Mode of action - These antimicrobials are analogues of para-aminobenzoic acid and competitively inhibit formation of dihydropteroic acid.
• Spectrum of activity - Broad range activity against gram-positive and gram-negative bacteria; used primarily in urinary tract and Nocardia infections.
• Resistance - Common
• Combination therapy - The sulfonamides are used in combination with trimethoprim; this combination blocks two distinct steps in folic acid metabolism and prevents the emergence of resistant strains.
03/21/13 19GKM/BIO319:Antibiotics/Sem2/2013
Trimethoprim, Methotrexate, Pyrimethamine (bacteriostatic)
• Mode of action - These antimicrobials binds to dihydrofolate reductase and inhibit formation of tetrahydrofolic acid.
• Spectrum of activity - Broad range activity against gram-positive and gram-negative bacteria; used primarily in urinary tract and Nocardia infections.
• Resistance - Common
• Combination therapy - These antimicrobials are used in combination with the sulfonamides; this combination blocks two distinct steps in folic acid metabolism and prevents the emergence of resistant strains.
03/21/13 20GKM/BIO319:Antibiotics/Sem2/2013
Sulfonamides
• Analogues of para-aminobenzoic acid
• Broad spectrum• Competitive inhibitors of
dihydropteroate synthase – needed for folic acid synthesis
Gerhard Domagk gets a Nobel Gerhard Domagk gets a Nobel for Medicine, 1939.for Medicine, 1939.
03/21/13 21GKM/BIO319:Antibiotics/Sem2/2013
Sulfonamides• Mostly absorbed from GI tract• Binds variably to serum albumin • Wide tissue distribution, including
transplacentally• Variably inactivated in liver by
acetylation and then excreted in urine
• Some agents can precipitate in acid urine
03/21/13 22GKM/BIO319:Antibiotics/Sem2/2013
1. Rapidly Absorbed and Eliminated Sulfonamides
• Sulfisoxazole, sulfamethoxazole, sulfadiazine
• Bind extensively to plasma proteins
• Highly concentrated in urine (cidal)
• Sulfamethoxazole combined with trimethoprim (Bactrim) is widely used to treat a variety of infections (esp. UTI)
03/21/13 23GKM/BIO319:Antibiotics/Sem2/2013
2. Poorly Absorbed Sulfonamides
• E.g. Sulfasalazine• Poorly absorbed in GI tract• Used to treat ulcerative colitis
and irritable bowel syndrome• Gut flora metabolize drug into
2 compounds, 1 toxic- sulfapyridine, 1 therapeutic (5-aminosalicylate)
• Hence is a prodrug – effective after breakdown
Ulcerative Colitis
03/21/13 24GKM/BIO319:Antibiotics/Sem2/2013
Sulfonamides for Topical Use
• E.g. 1.Sulfacetamide– Good penetration in eye
– Non-irritating
• 2. Silver sulfadiazine– Prevention and treatment of
burn wound infections
Bacterial corneal infectionBacterial corneal infection
03/21/13 25GKM/BIO319:Antibiotics/Sem2/2013
Long Acting Sulfonamide
• Serum half-life is measured in days rather than minutes or hours
• E.g. Sulfadoxine
• Combined with pyirethamine to treat malaria
Plasmodium vivaxPlasmodium vivax
03/21/13 26GKM/BIO319:Antibiotics/Sem2/2013
Therapeutic Uses of Sulfonamides
• Urinary tract infections• Nocardiosis -serious infection
caused by a fungus-like bacterium that begins in the lungs and can spread to the brain.
• Toxoplasmosis - caused by protozoan (avoid using in pregnant women)
Nocardia asteroidesNocardia asteroides
03/21/13 27GKM/BIO319:Antibiotics/Sem2/2013
Toxicity/Contraindications of Sulfonamides - UT
• Crystallization in acid urine– Common to uncommon
depending on drug.
– Alkalize urine or increase hydration
03/21/13 28GKM/BIO319:Antibiotics/Sem2/2013
Toxicity/Contraindications of Sulfonamides - blood
• Acute hemolytic anemia – Rare to extremely rare
– Associated with glucose-6-phosphate dehydrogenase activity in RBC
• Agranulocytosis - failure of the bone marrow to make enough white
blood cells (neutrophils). (extremely rare)
• Aplastic anemia - marrow doesn't make enough new blood cells.
(extremely rare)
03/21/13 29GKM/BIO319:Antibiotics/Sem2/2013
Toxicity/Contraindications of Sulfonamides - immune
• Hypersensitivity reactions (common to uncommon)– Skin and mucous membrane
manifestations (rashes)– Serum sickness - type III hypersensitivity
reaction that results from the injection of heterologous or foreign protein or serum
– Focal or diffuse necrosis of the liver (rare)
03/21/13 30GKM/BIO319:Antibiotics/Sem2/2013
Toxic Epidermal Necrolysis (TEN)
03/21/13 31GKM/BIO319:Antibiotics/Sem2/2013
Toxicity/Contraindications of Sulfonamides - miscellaneous
• Nausea, anorexia, vomiting (common)
• Kernicterus; damage caused by excessive jaundice– Displacement of bilirubin from
plasma albumin to brain resulting in encephalopathy(disease of the brain)
– Never give sulfa drugs to a pregnant or lactating woman
• Potentiation of oral coagulants, sulfonylurea hypoglycemic drugs, and hydrantoin anticonvulsants
Bilirubin deposits in neonatal Bilirubin deposits in neonatal brainbrain
03/21/13 32GKM/BIO319:Antibiotics/Sem2/2013
INJURY TO THE PLASMA MEMBRANE - Brief
• All cells are bound by a cell membrane. • And although the membranes of all cells are quite
similar, those of bacteria and fungi differ from eukaryotic cells.
• These slight differences allow for selective action of some antimicrobial agents.
• Certain antibiotics, like polymyxins, act as detergents to dissolve bacterial cell membranes by binding to phospholipids present in the membranes.
03/21/13 GKM/BIO319:Antibiotics/Sem2/2013 33
Antibiotic Resistance• A variety of mutations can lead to antibiotic resistance
• Mechanisms of antibiotic resistance
1. Enzymatic destruction of drug
2. Prevention of penetration of drug
3. Alteration of drug's target site
4. Rapid ejection of the drug
• Resistance genes are often on plasmids or transposons that can be transferred between bacteria.
03/21/13 34GKM/BIO319:Antibiotics/Sem2/2013
Transmission of drug resistance
• Transmission of drug resistance – Bacterial plasmids – Transposons – Bacteriophages
03/21/13 GKM/BIO319:Antibiotics/Sem2/2013 35
Resistance to Antibiotics
03/21/13 36GKM/BIO319:Antibiotics/Sem2/2013
Role of “misuse”
• Misuse of antibiotics selects for resistance mutants.
• Misuse includes;– Using outdated or weakened antibiotics– Using antibiotics for the common cold and other
inappropriate conditions– Using antibiotics in animal feed– Failing complete the prescribed regimen– Using someone else's leftover prescription
03/21/13 37GKM/BIO319:Antibiotics/Sem2/2013
Microbe Library
American Society for Microbiology
www.microbelibrary.org
03/21/13 38GKM/BIO319:Antibiotics/Sem2/2013
Antimicrobial Drug ResistanceMechanisms
• Altered permeability– Altered efflux
• tetracycline
Microbe Library
American Society for Microbiology
www.microbelibrary.org
03/21/13 39GKM/BIO319:Antibiotics/Sem2/2013
Antimicrobial Drug ResistanceMechanisms
• Inactivation– β-lactamase– Chloramphenicol
acetyl transferase
Microbe Library
American Society for Microbiology
www.microbelibrary.org
03/21/13 40GKM/BIO319:Antibiotics/Sem2/2013
Antimicrobial Drug ResistanceMechanisms
• Altered target site– Penicillin binding proteins
(penicillins)– RNA polymerase (rifampin)– 30S ribosome
(streptomycin)
Microbe Library
American Society for Microbiology
www.microbelibrary.org
03/21/13 41GKM/BIO319:Antibiotics/Sem2/2013
Antimicrobial Drug Resistance Mechanisms
• Replacement of a sensitive pathway– Acquisition of a resistant enzyme
(sulfonamides, trimethoprim)
03/21/13 42GKM/BIO319:Antibiotics/Sem2/2013
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