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UCSD BIMM 118 - Lecture 16

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Chemotherapeutic AgentsAntibioticsSlide 3Slide 4Slide 5Antibiotics - Cell wall synthesis inhibitorsSlide 7Slide 8Slide 9Slide 10Slide 11Slide 12Slide 13Slide 14Slide 15Slide 16Antibiotics - Protein synthesis inhibitorsSlide 18Slide 19Slide 20Slide 21Slide 22Slide 23Antibiotics - Folate AntagonsitsAntibiotics - Folate AntagonistsSlide 26Antibiotics - QuinolonesSlide 28Antibiotics - SummaryBIMM118Chemotherapeutic Agents•Antibiotics•Antifungals•Antivirals•Antiprotozoal•Antihelmintics•Anticancer drugsBIMM118AntibioticsGeneral Aspects:•Principle: inhibit growth of bacteria without harming the host– Drug must penetrate body tissue to reach bacteria (exception: GI infection)(unique targets: cell wall, protein synthesis, metabolic pathways…)–Bacteria targeted must be within the spectrum of the AB–Drug can be bactericidal or bacteriostatic–Different agents can be combined for synergistic effect (Note: not all combinations are useful, e.g. cell wall synthesis inhibitors loose effectiveness when combined with bacteriostatic drugs)–Identification of the invasive microorganism necessary for optimal treatment•General side effect: Alteration in normal body flora– GI tract harbors symbiotic bacteria which are killed by AB =>resistant bacteria repopulate the niche = secondary or superinfection(most common: overgrowth of Clostridium difficile)BIMM118Antibiotics•Resistance: loss of efficacy of a given AB against a particular strain– Frequently: Staphylococcus aureus, pseudomonas aeruginosa, mycobacterium tuberculosiiAcquisition:–Spontaneous mutation–Adaption: drug metabolism (-lactamase); alternative metabolic pathways–Gene transfer: plasmids (via conjugation and transduction); transposonsManifestation:–Microbes may increase manufacture of drug-metabolizing enzymes (penicillins)–Microbes may cease active uptake of certain drugs (tetracyclines)–Changes in receptors which decrease antibiotic binding and action–Microbes may synthesize compounds that antagonize drug actions–Antibiotic use promotes the emergence of drug-resistant microbes (especially the use of broad-spectrum antibiotics)!!! The more ABs are used, the greater the chance of resistance !!!BIMM118Antibiotics•Resistance avoided/delayed by: –Using AB only when absolutely needed and indicated:AB often abused for viral infections (diarrhea, flu-symptoms, etc.)–Starting with narrow-spectrum drugs–Limiting use of newer drugs–(Minimizing giving antibiotics to livestock)–Identifying the infecting organism–Defining the drug sensitivity of the infecting organism–Considering all host factors: site of infection, inability of drug of choice to penetrate the site of infection, etc.–Using AB combinations only when indicated: Severe or mixed infections, prevention of resistance (tuberculosis)Worldwide more than 500 metric tons antibiotics are used anually !!!BIMM118AntibioticsClassification:•Cell wall synthesis inhibitors – Beta-lactams (penicillins, cephalosporins, aztreonam, imipenem)–Poly-peptides (bacitracin, vancomycin)•Protein synthesis inhibitors–Aminoglycosides–Tetracyclins –Macrolides–Chloramphenicol–Clindamycin•Folate antagonists– Sulfonamides–Trimethoprim•QuinolonesBIMM118Antibiotics - Cell wall synthesis inhibitorsBacterial cell wall:Three types:•Gram-negative (e.g. E.coli, Salmonella) –Few peptidoglycan layers (Lipopolysaccheride)•Gram-positive (e.g. Staphylococci, Listeria) –Many peptidoglycan layers(Lipoteichoic acid)–Stains w/ crystal-violet/iodine•Acid-fast positive (Mycobacteria)–Cell wall contains waxy substance(Mycolic acid)–Stain w/ acid fast test (heating required)BIMM118Antibiotics - Cell wall synthesis inhibitorsBeta-lactam antibiotics:1928 - Alexander Fleming observes the antibacterial effects of Penicillin1940 - Florey and Chain extract Penicillin Classification:•Penicillins–Narrow spectrum – penicillinase sensitive–Narrow spectrum – penicillinase resistant–Broad spectrum penicillins–Extended-spectrum penicillins•Cephalosporines•Carbapenems•Monobactams •Vancomycin, BacitracinQuickTime™ and aTIFF (Uncompresse d) decompress orare need ed to see this picture.BIMM118Antibiotics - Cell wall synthesis inhibitorsPenicillinsInhibit transpeptidase required for cross-linking peptidoglycan chainsAlso inactivate an inhibitor of an autolytic bacterial enzyme => lysisNarrow spectrum – penicillinase (= -lactamase) sensitive•Benzylpenicillin–Naturally occuring–Poor oral availability (sensitive to stomach acid)=> given by injection–Active against gram-positive bacteria•Phenoxymethylpenicillin–Better oral availability (acid resistant)BIMM118Antibiotics - Cell wall synthesis inhibitorsNarrow spectrum – penicillinase (= -lactamase) resistant•Methicillin–Semisynthetic–Poor oral availability (only parenteral)–Active against gram-pos bacteria–Mostly used for Staphylococcus aureus•Oxacillin–Good oral availability•Cloxacillin•DicloxacillinBIMM118Antibiotics - Cell wall synthesis inhibitorsBroad spectrum – penicillinase (= -lactamase) sensitive(= Aminopenicillins)•Ampicillin–Semisynthetic–Good oral availability –Active against gram-pos and gram-neg bacteria–Active against enterobacteria•Amoxicillin–Excellent oral availabilityBIMM118Antibiotics - Cell wall synthesis inhibitorsExtended spectrum – penicillinase (= -lactamase) sensitive(= Carboxypenicillins)•Carbenicillin–Semisynthetic–Poor oral availability –Active against gram-pos and gram-neg bacteria–Active against Pseudomonas aeruginosa, Klebsiella •Ticarcillin•Mezlocillin•PipercillinBIMM118Antibiotics - Cell wall synthesis inhibitorsCephalosporinesDerived from Cephalosporium sp. (same antibiotic mechanism as penicillins)Cross-allergies with penicillins are commonSome CSs antagonize Vitamin K => bleedingSome CSs block alcohol oxidation => disulfiram effectClassified into generations:•1-4•Increasing activity against gram-negative bacterial and anaerobes•Increasing resistance to destruction by beta-lactamases•Increasing ability to reach cerebrospinal fluidBIMM118Antibiotics - Cell wall synthesis inhibitorsFirst generation – -lactamase sensitive•Cefazolin–Naturally occuring–Active against gram-positive bacteria•CephalexinSecond generation – -lactamase sensitive•Cefaclor–Some activity against gram-neg bacteria•Cefamandole•CefoxitinBIMM118Antibiotics -


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UCSD BIMM 118 - Lecture 16

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