MMG301 1st Edition Lecture 20Outline of Last Lecture I. Bacterial resistanceOutline of Current Lecture II. AntibioticsCurrent Lecture-non-chemotherapeutic agents: non-selective, too toxic for internal use-chemotherapeutic agents-synthetic agents – most are synthetic growth factor analogs (blocks pathway to stop growth by mimicking)-antibiotics: natural compounds, produced by nature (not synthetic)-selective toxicity-minimum effective dose (ED): minimum dose that cures 50% of the host-lethal dose (LD): dose that causes 50% death of the host-therapeutic index = LD50 / ED50 Can go from 2 to 100-higher is better, means safer it is-as few side effects as possible-synthetic antimicrobial drugs: first one developed was Salvarsan (Paul Erhlich, 1910): an arsenicderivative to treat syphilis, had many side effects-growth factor analogs -inhibitors of folic acid (vitamin) biosynthesis-sulfa drugs (Gerhard Domagk, 1935)-folic acid: precursor of nucleotidesThese notes represent a detailed interpretation of the professor’s lecture. GradeBuddy is best used as a supplement to your own notes, not as a substitute.-sulfanilamide-mode of action: block incorporation of aminobenzoic acid in folic acid-selective agents: animals don’t have that pathway, so it targets bacteria only-limitations: bacterial resistance and allergies-cell wall synthesis inhibitor -mycolic acid-isoniazid: analog of nicotinamide-treatment of tuberculosis (most effective single drug, often used in combination with other drugs)-narrow spectrum: targets mycobacterium only-limitation: bacteria often become resistant-inhibitors of DNA packaging-DNA gyrase and topoisomerase-fluoroquinolone drugs: analogs of nucleotides, block the action of DNA gyrase and topoisomerase by binding to enzymes but not doing anything-broad spectrum: active on large number of bacterial species-Ciprofloxacin (Cipro)-limitations: side effects for some people-antibiotics-antibiotics: target many different pathways-mechanisms: vitamin synthesis, protein synthesis, DNA/RNA synthesis, cell wall synthesis, cell membranes-beta-lactam antibiotics-produced by fungi-b-lactam ring – all have the 4 member ring, target peptidoglycan cell wall-Penicillin G was the first one developed-against Gram+ because peptidoglycan is exposed, gram- is often resistant-other b-lactams-mode of action: -prevent transpeptidase reaction: forms a complex (transpeptidase + b-lactam) that induces the synthesis of autolysins; prevents synthesis of new peptidoglycan-autolysins: degrade the pre-existing peptidoglycan-antibiotics that inhibit protein synthesis-Streptomyces and other bacteria-bind to the ribosome-broad-spectrum (gram+ and gram-)-Tetracyclines -tetrahydrocarbon rings-largest spectrum of all antibiotics-safe, little to no side effects-fed to swine and poultry to prevent/cure disease-resistance with efflux pump, membrane becomes impermeable, ribosome mutations -Aminoglycosides-amino sugars with glycosidic bonds-limitations: severe side effects (liver damage and neurotoxic)-reserve antibiotics-Macrolides-lactone rings linked to sugars, bind ribosomes-also have efflux pumps -Erythromycin-uses: gram+ bacteria mostly-antibiotics interfering with membrane properties-produced by Streptomyces species-against Gram+-Daptomycin – Cyclic lipopeptide-Ionophore antibiotic: creates pores in the membrane, cells will no longer have a source of ATP and will die-limitations: she doesn’t remember-Platensimycin – Inhibits fatty acid biosynthesis-spectrum: works on a lot of bacteria-experimental drug: you need a lot of it-antibiotic drug resistance1. Antibiotic inactivation: happens through the action of enzymes produced by the cell (example: b-lactamase, acetylases, phosphatases)2. Altered target: target becomes resistant (example: lipid membranes, ribosome mutants)3. Metabolic bypass: fluoroquinone targets folic acid synthesis, but bacteria have developed transporters for folic acid to uptake it from the environment (bypassed the pathway of making it4. Efflux pump: pumps the antibiotic out, it can’t stay in the cell long enough to effect it5. Impermeability: cell membrane changes structure so the antibiotic cant come in-R plasmids: plasmids are inherited by daughter cells, plasmids are smaller than chromosomes, so when bacterial conjugation occurs (bacteria share DNA) plasmids slip through; R plasmids carry genes for antibiotic
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