History
Antibiotics
Targets (1/2)
Targets (2/2)
Resistance
100
Paul Erlich: Name/Describe the theory, origin, drug, disease, and year of nobel
Theory: Wanted to find compound that would act as a "Magic Bullet", only killing bacteria; chemicals with selective toxicity; chemotherapy Origin: selective stains (histology) Drug: Arsphenamine (1910), #606 Salvarsan Disease: Syphilis (Trepanoma palladium) Nobel: 1908 (previous immunological work)
100
What is the difference between bactericidal and bacteriostatic? Name antimicrobial agents for each.
Bactericidal: kills bacteria and, ideally, nothing else e.g. Aminoglycosides, Beta-Lactams, Vancomycin, Quinolones, Rifampin, Metronidazole Bacteriostatic: limit the growth of bacteria by interfering with bacterial protein production, DNA replication, or other aspects of bacterial cellular metabolism e.g. Chloramphenicol, Erythromycin, Clindamycin, Sulfonamides, Trimethoprim, Tetracyclines
100
Name/Describe the three classes of antimetabolites.
Antimetabolites act as substrate analogues mimicking something the bacteria normally binds to 1. Sulfonamides: compete with bacterial p-Amino Benzoic Acid (PABA) to inhibit folic acid synthesis 2. Trimethoprim: directly inhibits folic acid synthesis (dihydrofolate reductase) 3. Trimethoprim + Sulfamethoxazole: synergistic combination useful against UTIs
100
Name/Describe inhibitors of protein synthesis (50S).
Chloramphenicol & Macrolides (Erythromycin) - Bind REVERSIBLY to 50S subunit and blocks the translocation step - Chloramphenicol → broad spectrum but toxic - Macrolides (Erythromycin) → broad spectrum, non-toxic (common for children, well-tolerated) Clindamycin - Binds REVERSIBLY to 50S subunit - Interferes with binding of the amino acid acyl-tRNA complex inhibiting peptidyl transferase - Works best against Staphylococcus and anaerobic G- rods - Used for penicillin allergic people
100
Discuss: Entry/Exit
Lack of entry, so they cannot get into target. OR Greater exit, like efflux pumps to pump out antibiotic.
200
Gerhard Domagk: Name/Describe the theory, origin, drug, disease, and year of Nobel
Theory: Drugs are changed in the body Origin: Prontosil (only active in vivo) Drug: Sulfonamide (1935) Disease: Streptococcus (but broad spectrum) Nobel: 1939 (1947)
200
Compare LD50 and ED50. How do they relate to the Therapeutic Ratio?
LD50: Dose that kills 50% of test animals (Lethal Dose) ED50: Dose that is effective in 50% of the test population (Effective Dose) Therapeutic Ratio = LD50/ED50 OR Therapeutic Ratio = the ratio between the median lethal dose and median effective dose The bigger the value, the better the antibiotic.
200
Name/Describe toxins used against cell wall synthesis?
Polymyxins: - Destroy membranes (like detergents and antibacterial peptides); insert into lipid bilayer to cause holes - Active against G- bacilli (because of outer cell membrane) - Serious side effects (may destroy own cell’s lipid bilayer) - Used mostly for skin and eye infections
200
Name/Describe inhibitors of DNA replication.
Metronidazole - Gets metabolized by bacteria in absence of oxygen into intermediate that causes breakage of DNA - Bactericidal - Active against anaerobes Fluoro-Quinolones - Inhibit DNA topoisomerases (DNA replication, so against actively growing bacteria) - Bactericidal - Quinolones: narrow spectrum, G- rods - Fluoro-Quinolones: broad spectrum, G+/-
200
Discuss: Drug Inactivation
Enzymes that modify drug and make it inactive: - Beta-lactamases - CAT (chloramphenicol acetyl transferase) - Aminoglycosides and transferases
300
Alexander Fleming: Name/Describe the theory, origin, drug, disease, and year of Nobel
Theory: Microbes make antibiotics Origin: mold Penicillium notatum Drug: Penicillin (1928) Disease: Gram-positive bacteria Noble: 1945
300
Describe the 3 susceptibility tests.
1. MIC Broth dilution 2. MIC Agar dilution 3. Agar diffusion (Kirby-Bauer method) MIC: Minimum Inhibitory Concentration is the lowest concentration that inhibits growth of organisms Kirby-Bauer Disk-plate zones of inhibition depend upon: (1) pH of environment (2) Media components (agar depth, nutrients) (3) Stability of drug (4) Size of inoculum (5) Length of incubation (6) Metabolic activity of organisms
300
Name/Describe Beta-Lactams used against cell wall synthesis?
1. Bactericidal; effective on growing cells only 2. Drug links covalently to regulatory enzymes called PBPs (penicillin-binding proteins) 3. Blocks cross-linkage and/or elongation of peptidoglycan Penicillin (broad spectrum) Cephalosporins Carbapenems (broad spectrum) Monobactams (G- aerobic)
300
Name/Describe inhibitors of RNA synthesis.
Rifampin - Binds IRREVERSIBLY to RNA polymerase - Bactericidal - Rapid resistance development (co-treatment) - Active against G+ cocci and Mycobacterium (treatment and prevention of meningococcus)
300
Discuss: Altered Target
Altered… - RNA polymerase (mutants) - DNA topoisomerase/gyrase - Ribosomal proteins - Methylation of 23S rRNA - Penicillin binding protein (PBP)
400
Selman Waksman: Name/Describe the theory, origin, drug, disease, and year of Nobel
Theory: Soil Streptomyces make antibiotics; came up with antibiotic definition Origin: bacteria, Streptomyces Drug: Streptomycin Disease: Tuberculosis Nobel: 1952
400
What are the 6 conditions of an ideal drug?
1. Selective toxicity (high Therapeutic Ratio) 2. Bactericidal vs. bacteriostatic 3. Favorable pharmacokinetics (how the body absorbs, distributes, breaks down, and eliminates drugs) 4. Spectrum of activity 5. Lack of “side effects” 6. Little resistance development
400
Name/Describe non-Beta-Lactams used against cell wall synthesis?
Vancomycin (glycopeptides) - Interferes with PG crosslinking and elongation - Active against G+ cocci, but not G- Bacitracin (polypeptide) - Inhibits bactoprenol (no PG elongation) Ethambutol and Isoniazid - Inhibits enzymes that catalyze cell wall synthesis - Mycobacterial infections
400
What is a summary of the post-antibiotic/vaccine era (1969)?
Surgeon General William Stewart stated it was time to “close the book on infectious diseases.”
400
Discuss: Synthesis of Resistant Pathway
Plasmid has gene for DHF reductase; insensitive to Trimethoprim
500
Name/Describe in chronological order the 5 scientists who led to the discovery of antibiotics?
A. Fleming, 1928: first description of Penicillin (accidental discovery) R. Dubos, 1938: first experimental design to screen for antibiotic (Gramicidin) Chain and Florey, 1938-1940: purification and application of Penicillin S. Waksman, 1944: discovery of Streptomycin (Tuberculosis)
500
What are the 5 transport steps required for antibiotic activity, and where in those steps are potential points of interference for bacteria?
1. Anatomic approximation 2. Surface Binding (adsorption) → interference 3. Intracellular Uptake → interference 4. Target Binding → interference 5. Growth Inhibition OR Lysis/Death → interference
500
Name/Describe inhibitors of protein synthesis (30S).
Aminoglycosides (e.g. Tobramycin, Amikacin, Streptomycin) - Bind IRREVERSIBLY to bacterial ribosome on 30S subunit blocking formation of initiation complex - Leads to mis-incorporation of amino acids - Mostly bactericidal - Broad-spectrum (G- rods, Pseudomonas aeruginosa, Neisseria gonorrhea, bowel pre-surgery) Tetracyclines (against Chlamydia) - Bind REVERSIBLY to 30S subunit, interferes w/ attachment of tRNA-carrying amino acids to ribosome - Broad-spectrum - Bacteriostatic
500
Review: Name the 6 targets of antibiotics and the classes of drugs for each.
Antimetabolites: Sulfonamides, Trimethoprim Cell Wall Synthesis: Beta-lactams, Vancomycin, Isoniazid, Bacitracin, Polymyxin Protein Synthesis 30S: Aminoglycosides, Tetracylcines Protein Synthesis 50S: Chloramphenicol, Macrolides, Clindamycin DNA Replication: Quinolones, Metronidazole RNA Synthesis: Rifampin
500
Discuss: Genetic vs. Non-Genetic Origin of Resistance
Non-Genetic: metabolic inactivity (Mycobacteria), cell wall (G-, capsule), biofilm (Pseudomonas) Genetic: spontaneous mutation of old genes (Vertical evolution) vs. acquisition of new genes (Horizontal) - Chromosomal resistance (phage/transposons) - Extrachromosomal resistance (plasmids)
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