药物微生物与宿主化学疗法的元素（英文ppt）drugsmicrobes host the elements of

Drugs, Microbes, Host The Elements of Chemotherapy Chapter 12 Copyright The McGraw-Hill Companies, Inc) Permission required for reproduction or display. To run the animations you must be in Slideshow View. Use the buttons on the animation to play, pause, and turn audio/text on or off. Please note: once you have used any of the animation functions (such as Play or Pause), you must first click in the white background before you advance the next slide. Antibiotics - Still Miracle Drugs 3 A brief history of antibiotics n 1495, mercury to treat syphilis. n 1630, quinine (chinchona tree) for malarial fever by South American Indians. n 1910, Paul Ehrlich developed arsenical compound (Salvarsan) for syphilis, term: the chemical knife. n 1929, Alexander Fleming found penicillin. n 1940, Ernst Chain and Howard Flory demonstrated the effect of penicillin. n 1940-1970, search for new antibiotics n Recent years: modifying old drugs, finding new discipline in combating antibiotics resistanceFor lecture only BC Yan g Historical Perspective 100 years ago- 1 in 3 children died of infectious disease before age 5 Germ theory of disease Kochs postulates Robert Ehrlich- microbe specific dyes Sir Alexander Flemming-discovered penicillin (1929) Paul Ehrlichs “Magic Bullet” Concept Salvarsan No. 606 Plate of Staphylococcus aureus inhibited by Penicillium notatum Flemming and Penicillin Principles of Antimicrobial Therapy Goal of antimicrobial chemotherapy: administer a drug to an infected person, which destroys the infective agent without harming the hosts cells Rather difficult to achieve this goal Chemotherapeutic agents described with regard to their: origin range of effectiveness naturally produced or chemically synthesized Antibiotics Topics - Antimicrobial Chemotherapy - Selective Toxicity - Survey of Antimicrobial Drugs - Microbial Drug Resistance - Drug and Host Interaction The Origins of Antimicrobial Drugs Antibiotics metabolic products of aerobic bacteria and fungi reduce competition for nutrients and space Bacteria: Streptomyces ,Acromyces and Bacillus Molds: Penicillium and Cephalosporium Chemists have created new drugs by altering the structure of naturally occurring antibiotics Selective Toxicity Drugs that specifically target microbial processes, and not the human host cellular processes. Selective Toxicity Mechanisms and sites Mechanism of action Bacterial cell wall Nucleic acid synthesis Protein synthesis Cell membrane Folic acid synthesis Targets of Antimicrobials 1. Cell wall inhibitors Block synthesis and repair Penicillins Cephalosporins Carbapenems Vancomycin Bacitracin Fosfomycin Isoniazid 2. Cell membrane Causelossofselective permeability Polymyxins Daptomycin 3. DNA/RNA Inhibit replication and transcription Inhibit gyrase(unwinding enzyme) Quinolones Inhibit RNA polymerase Rifampin Ribosome mRNA DNA 4. Protein synthes is inhibitors acting on ribosomes Site of action 50S subunit Erythromycin Clindamycin Synercid Pleuromutilins Site of action 30S subunit Aminoglycosides Gentamicin Streptomycin Tetracyclines Glycylcyclines Both 30S and 50S Blocks initiation of protein synthesis Linezolid 5. Folic acid synthesis Block pathways and inhibit metabolism Sulfonamides (sulfa drugs) Trimethoprim Substrate Enzyme Product Mechanisms of Drug Action Inhibition of cell wall synthesis Inhibition of nucleic acid structure and function Inhibition of protein synthesis Interference with cell membrane structure or function Inhibition of folic acid synthesis Antibiotics that block Cell wall synthesis Penicillin and Cephalosporins are -lactam antibiotics. Not very effective against Gram positive bacteria Active cells must constantly synthesize new peptidoglycan and transport to cell envelope. Penicillins and Cephalosporins react with one or more of the enzymes required to complete this process. (blocks transpeptidases involved in cross-linking the NAG NAM sugars) A bacterium damaged and distorted by penicillin The mechanism of action of penicillins and cephalosporins. -Lactam antibiotics bind to and competitively inhibiting the transpeptidase enzyme that cross-links PG layers. We have come a long way! Penicillin was being mass-produced by 1944. Penicillin Source: Penicillin chrysogenum Penicillin antibiotics grouped into generations based on spectrum of anti- microbial activity. (1st, 2nd , 3rd and 4th generations) Natural (penicillin G and V) Semisynthetic (Ampicillin, Carbenicillin) -lactam antibiotics These all share a common -lactam ring, shown in blue - The R group is responsible for the activity of the drug and can be changed to improve activity of the antibiotic. - Cleavage of the beta- lactam ring will render the drug inactive.bacteria have figured this out!. Chemical structure of penicillins Structure Thiazolidine ring Beta-lactam ring Variable side chain (R group) Penicillin resistance via penicillinase (b Lactamase) Some penicillin resistant organisms produce Penicillinase which degrades penicillin. Methicillin (-lactam antibiotic) Developed to treat, -lactamase producing organisms such as Staphylococcus aureus MRSA quickly evolved Methicillin unstable in gastric acid- discontinued Cephalosporin (b-Lactam Antibiotic) Cephalosporium acremonium (mold) Widely administered today Diverse group (natural and semisynthetic) 1st, 2nd, and 3rd generations Structure similar to penicillin except Main ring is different Two sites for R groups The different R groups allow for versatility and improved effectiveness. The structure of cephalosporins Antibiotics weaken the cell wall, cause the cell to lyse. Antibiotics that block Cell wall synthesis - effective against Methicillin Resistant Staphylococcus aureus (MRSA) - Vancomycin is a broad-spectrum antibiotic and often used after treatment with other antibiotics have failed Vancomycin hinders peptidoglycan elongation Antibiotics that block cell wall synthesis Cycloserine inhibits the formation of the basic peptidoglycan subunits - amino acid analog -effective against Mycobacterium tuberculosis Bacitracin Inhibits the transport of NAG and NAM across the cell membrane in the synthesis of peptidoglycan - Toxicity limits oral use - common ingredient of eye and skin antibiotic preparations Inhibition of Protein synthesis - Protein synthesis inhibitors generally broad spectrum, toxicity problems. Inhibitors of 50S ribosomal subunit Chloramphenicol Binds to the 50S ribosome Prevents peptide bond formation Macrolides e.g. Erythromycin Binds to the 50S ribosome Prevents peptide bond formation Chloramphenicol Inhibits protein synthesis Broad-spectrum Bacteriostatic Treat typhoid fever, brain abscesses Rarely used now due to serious side effects aplastic anemia Erythromycin Inhibits protein synthesis Broad-spectrum Commonly used as prophylactic drug prior to surgery Side effects - low toxicity Examples Aminoglycosides (Streptomycin, neomycin, gentamycin) Bind to the 30S ribosome Causes Misreading of mRNA Tetracyclines - Block attachment of tRNA Inhibitors of 30S ribosomal subunit Aminoglycosides From Streptomyces Inhibit protein synthesis Streptomyces synthesizes many different antibiotics such as aminoglycosides, tetracycline, chloramphenicol, and erythromycin. Tetracycline Inhibits proteins synthesis Broad spectrum and low cost Commonly used to treat sexually transmitted diseases Minor side effect gastrointestinal disruption Aminoglycoside Sites of inhibition on the procaryotic ribosome Polymyxin B - Bactericidal to most Gram negatives - Disrupts cell membrane and makes it more permeable Topical ONLY - Neurotoxic Combined with bacitracin and neomycin (broad spectrum) in over-the-counter preparation (Neosporin) Injury to the Plasma Membrane Rifamycin Binds to prokaryotic RNA Polymerase and inhibits RNA synthesis Antituberculosis Quinolones and fluoroquinolones Ciprofloxacin Serious adverse events occur more commonly with fluoroquinolones than with any other antibiotic drug classes. Inhibits DNA gyrase Urinary tract infections Inhibitors of Nucleic Acid Synthesis Folic acid synthesis (vitamin B9) Sulfonamides (sulfa drug) and trimethoprim Synthetic analogs Competitive inhibition of key enzymes Prevents the metabolism of DNA, RNA, and amino acid Sulfa allergies are common prescribed carefully Sulfonamides compete with PABA for the active site on the enzyme. The sulfonamide Sulfamethoxazole is commonly used in combination with trimethoprim. Folic acid is essential to synthesize DNA, repair DNA, and methylate DNAGood target! Broad vs. narrow spectrum drugs Antivirals Increasing types of drugs becoming available However, it is difficult to maintain selective toxicity Augment Host Self-Defense System Interferon genetically engineered antiviral protein from a human gene Vaccines Antivirals Unlike most antibiotics, antiviral drugs do not destroy their target pathogen- instead they inhibit their development. Effective drugs target viral infection and replication cycle Entry Nucleic acid synthesis Assembly/release Antivirals Most antivirals now available target: - HIV - herpes virus - hepatitis B and C - influenza A and B viruses Anti-viral resistant strains exist Antiviral drug structures and their unique modes of action. Antiviral drug structures and their unique modes of action. Antiviral drug structures and their unique modes of action. Other types of antimicrobials Antifungal ketoconizole Antiprotozoan metronidazole Treat giardiasis Antimalarial Quinine Plasmodium falciparum malaria Antihelminthic mebendazole Tapeworms, roundworms Giardia Antimicrobial Resistance Relative or complete lack of effect of antimicrobial against a previously susceptible microbe Enzymatic destruction of drug Prevention of penetration of drug Alteration of drugs target site Rapid ejection of the drug Mechanisms of Antibiotic Resistance Mechanisms of Antibiotic Resistance Ways to acquire resistance Figure 20.20 Antibiotic Resistance Figure 20.20 Antibiotic Resistance Intermicrobial transfer of plasmids containing resistance genes (R factors) occurs by conjugation, transformation,and transduction What Factors Promote Antimicrobial Resistance? Exposure to sub-optimal levels of antimicrobial Inappropriate use Exposure to microbes carrying resistance genes Inappropriate Antimicrobial Use Prescription not taken correctly Antibiotics for viral infections Antibiotics sold without medical supervision Spread of resistant microbes in hospitals due to lack of hygiene Inappropriate Antimicrobial Use Inadequate surveillance or defective susceptibility assays Poverty or war Use of antibiotics in foods Lack of quality control in manufacture or outdated antimicrobial Antibiotics in Foods Antibiotics are used in animal feeds and sprayed on plants to prevent infection and promote growth Multi drug-resistant Salmonella typhi has been found in 4 states in 18 people who ate beef fed antibiotics Antibiotic Drug and Host Interaction Toxicity to organs Allergic reactions Suppress/alter microflora Effective drugs Tetracycline treatments can cause teeth discoloration. Disrupting the normal flora in the intestine can result in superinfections. Finding an effective drug for trreatment Identify infectious agent Perform sensitivity testing Often the Minimum Inhibitory Concentration (MIC) is determined The Kirby-Bauer Test. S