Chapter 6: The Elements of Chemotherapy
Chapter 6: The Elements of Chemotherapy 2420
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This 4 page Class Notes was uploaded by Siân L'Roy on Sunday August 21, 2016. The Class Notes belongs to 2420 at Tarrant County College District taught by Mark Pulse in Summer 2016. Since its upload, it has received 4 views. For similar materials see Microbiology in Biology at Tarrant County College District.
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Date Created: 08/21/16
The Elements of Chemotherapy (Antibiotics) Alexander Fleming was one of the first scientist to recognize the importance of antibiotic treatment for lifethreatening infections o In 1928 he observed a fungal contaminant that inhibited the growth of S. aureus on plate cultures o He determined the fungus to be a species of Penicillium; he identified the new inhibitory agent as pencillin o Fleming observed that penicillin was effective against several species of bacteria, and was minimally toxic to the host (animals) o He was not able to successfully purify penicillin; this was accomplished by Chain and Florey in the 1940’s Penicillin was mass produced for use in WWII Prior to penicillin, more soldiers died from woundassociated infections than from the instruments of war (bullets) themselves In 1900, 1 out of 100 infected individuals died in the United States; by 1990, the frequency dropped to 1 in every 300 infected individuals Sir Alexander Fleming (18811955) Lecturer at Saint Mary’s Medical School (London, England) Research focused on identifying products that inhibited bacterial growth Discovered lysozyme in 1923 (hydrolyzes cell walls) Accidently discovered penicillin in 1928 o Penicillin Discovery He noticed that Staphylococcus aureus growth was inhibited near a mold contaminant He identified the mold as a Penicillium notatum Named the inhibitory agent of penicillin Published findings in the British Journal of Experimental Pathology in 1929 Fleming was not able to successfully purify penicillin in the lab Howard Florey and Ernest Chain Headed research team at Oxford University in England The Elements of Chemotherapy (Antibiotics) Selected penicillin in 1938 as a possible treatment for bacterial infections Designed a method to purify penicillin in 1940 Performed animal test to validate the activity of penicillin within an infected host o Early uses of purified penicillin First human patient dosed with penicillin in February 1941 (Albert Alexander) Five patients with infections dosed with penicillin 4 out of the 5 fully recovered Results published in 1941 (The Lancet) Full industrial scale up in the United Kingdom and the United States Penicillin was available on DDay (WWII) landing in June 1944 Based on their macromolecular activities, most antibiotics belong to 1 of 6 antibiotic classes 1. Cell wall synthesis inhibitors: Includes βlactams (penicillin), glycopeptides (vancomycin), bacitracin, and phosphonomycin; all prevent the formation of the cell wall in dividing cells 2. Protein synthesis inhibitors: Includes aminoglycosides (gentamicin), tetracyclines (tetracycline), and macrolides (erythromycin); all directly inhibit protein synthesis by binding to the ribosome 3. DNA replication inhibitors: Includes fluoroquinolones (ciprofloxacin) and metronidazole; fluoroquinolones bind to DNA gyrase to prevent DNA replication, while metronidazole generates nicks in a DNA strand 4. RNA synthesis inhibitor: Only rifampin belongs to this class; it binds to RNA polymerase and blocks transcription 5. Tetrahydrofolic acid synthesis inhibitors: Includes trimethoprim and sulfonamides; both are competitive inhibitors of tetrahydroflic acid production (needed for nucleic acid and fMet synthesis) 6. Cytoplasmic membrane damager: Daptomycin belongs to this class; it binds to and damages the cytoplasmic membrane of Gram (+) bacteria What is antibiotic resistance? The Elements of Chemotherapy (Antibiotics) An antibiotic cannot inhibit the growth of or kill bacteria Generated due to selective pressure associated with the over use of antibiotics It is a matter of survival for the bacterial cell Alexander Fleming warned of resistance developing to penicillin in his Nobel Prize Lecture in 1945, stating that, “It is not difficult to make microbes resistant to penicillin in the laboratory by exposing them to concentrations not sufficient to kill them, and the same thing has occasionally happened in the body.” By 1960 more than 80% of Staphylococci were resistant to penicillin **Bacteria are not just resistant to one antibiotic, but many are MultiDrug Resistant organisms (MDR) Antibiotic resistance has become more prevalent as a result of their use in medicine and other industries (agriculture) Resistance can be innate or acquired, and several mechanisms of resistance have been identified in bacteria Identified mechanisms of resistance include: o Production of drug inactivating enzymes E.g.: penicillinase is produced by bacteria (mostly Gram negative) that enzymatically inactivates penicillin o Modification to the target molecule or pathway E.g.: penicillin can no longer recognize modified penicillinbinding proteins (PBPs) involved in cell wall synthesis o Decreasing the influx/uptake of an antibiotic E.g.: Gramnegative bacteria can alter the structure of membrane associated porins (channels), effectively reducing the influx of an antibiotic o Increased elimination of internalized drug E.g.: Bacteria can upregulate (increase) the numbers of an efflux pump involved in ‘pumping’ an internalized antibiotic out of the cell The Elements of Chemotherapy (Antibiotics) Antibiotic resistance in bacteria can be acquired by spontaneous genetic mutations or by the horizontal transfer of resistance genes
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