PowerPoint Lecture Presentations prepared by Bradley W. Christian, McLennan Community College. Antimicrobial Drugs Pearson Education, Ltd.
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1 PowerPoint Lecture Presentations prepared by Bradley W. Christian, McLennan Community College CHAPTER 20 Antimicrobial Drugs 2016 Pearson Education, Ltd.
2 Selective toxicity: selectively finding and destroying pathogens without damaging the host. Chemotherapy: the use of chemicals to treat a disease. Antibiotic: a substance produced by a microbe that, in small amounts, inhibits another microbe. Antimicrobial drugs: synthetic substances that interfere with the growth of microbes.
3 The History of Chemotherapy 1928: Fleming discovered penicillin, produced by Penicillium. 1932: Prontosil red dye used for streptococcal infections. 1940: Howard Florey and Ernst Chain performed first clinical trials of penicillin. Today there is a growing problem of antibiotic resistance. Figure 20.1 Laboratory observation of antibiosis.
4 Staphylococcus aureus Fleming and Penicillin Penicillium notatum
5 Table 20.1 Representative Sources of Antibiotics 2016 Pearson Education, Ltd.
6 The Spectrum of Antimicrobial Activity Narrow spectrum of microbial activity: drugs that affect a narrow range of microbial types. Broad-spectrum antibiotics: affect a broad range of gram-positive or gram-negative bacteria. Superinfection: overgrowth of normal microbiota that is resistant to antibiotics.
7 The Spectrum of Antimicrobial Activity 分枝桿菌 Narrow spectrum Broad spectrum
8 The Action of Antimicrobial Drugs Bactericidal agent 殺菌劑 :Kill microbes directly Bacteriostatic agent 抑菌劑 :Prevent microbes from growing
9 Bacteria have their own enzymes for Cell wall formation Protein synthesis DNA replication RNA synthesis Synthesis of essential metabolites
10 Figure 20.2 Major Action Modes of Antibacterial Drugs Pearson Education, Ltd.
11 Inhibiting Cell Wall Synthesis Ex: Penicillin 青黴素 Prevent the synthesis of intact peptidoglycan Natural penicillins Semisynthetic penicillins
12 Figure 20.3 The inhibition of bacterial cell wall synthesis by penicillin Pearson Education, Ltd.
13 Inhibiting Protein Synthesis 氯黴素 鏈黴素 四環黴素 Figure 20.4 The inhibition of protein synthesis by antibiotics.
14 Injuring the Plasma Membrane Ex: polypeptide antibiotics Cause change in the permeability of the plasma membrane Ex: antifungal drugs amphotericin B, miconazole, ketoconazole Combine with sterols in the fungal plasma membrane to disrupt the membrane Figure 20.5 Injury to the plasma membrane of a yeast cell caused by an antifungal drug.
15 Inhibiting Nucleic Acid Synthesis This kind of drugs interfere the processes of DNA replication and transcription and have an extremely limited usefulness. Ex: rifampin and quinolone
16 Inhibiting the Synthesis of Essential Metabolites Competitively inhibition: a substance (antimetabolite) that closely resemble the normal substrate for the enzyme. Figure 5.7
17 Ex: antimetabolite sulfanilamide v.s. para-aminobenzoic acid (PABA) 磺苯醯胺 ( 磺胺類 ) 葉酸 many microorganisms synthesize folic acid from PABA, but human do not selective toxicity
18 Table 20.3 Antibacterial Drugs (1 of 2) 2016 Pearson Education, Ltd.
19 Table 20.3 Antibacterial Drugs (2 of 2) 2016 Pearson Education, Ltd.
20 Table 20.4 Differential Grouping of Cephalosporins 2016 Pearson Education, Ltd.
21 Table 20.5 Antifungal, Antiviral, Antiprotozoan, and Antihelminthic Drugs (1 of 2) 2016 Pearson Education, Ltd.
22 Table 20.5 Antifungal, Antiviral, Antiprotozoan, and Antihelminthic Drugs (2 of 2) 2016 Pearson Education, Ltd.
23 Common Antimicrobial Drugs Antibacterial Antibiotics: Inhibitors of Cell Wall Synthesis Penicillin: contain a β-lactam ring; Types are differentiated by the chemical side chains attached to the ring. Natural penicillins Figure 20.6a
24 Figure 20.7 Retention of penicillin G. Penicillin G (injected intramuscularly) Penicillin G (oral) Procaine penicillin Benzathine penicillin 2016 Pearson Education, Ltd.
25 Natural penicillins have some disadvantages: Narrow spectrum Susceptibility to penicillinases Figure 20.8
26 Semisynthetic penicillins: Contain chemically added side chains, making them resistant to penicillinases Figure 20.6b
27 Penicilinase-resistant penicillins Methicillin oxacillin, nafcillin were developed to against MRSA (methicillin-resistant Staphylococcus aureus) Extended-spectrum penicillins: Effective against gramnegatives as well as gram-positives Aminopenicillin (ex: ampicillin, amoxicillin) Carboxypenicillin (ex: carbenicillin, ticarcillin) Ureidopenicillin ( 脲基青黴素, 加上 H 2 NCONH-,ex: mezlocillin, azlocillin)
28 Aminopenicillin Penicillin Ampicillin Amoxicillin
29 Carboxypenicillin Penicillin Carbenicillin Ticarcillin
30 Ureidopenicillin Penicillin Azlocillin Mezlocillin
31 Penicillins plus -lactamase inhibitors Amoxicillin + potassium clavulanate Carbapenems Substitute a C for a S and add a double bond Monobactam
32 Cephalosporins 頭芽孢菌素抗生素 Work similar to penicillins β-lactam ring differs from penicillin Grouped according to their generation of development Figure 20.9
33
34 Polypeptide antibiotics Bacitracin 枯草桿菌素 Topical application Against gram-positives Vancomycin 萬古黴素 Glycopeptide Important "last line" against antibiotic resistant S. aureus
35 Antimycobacterial Antibiotics Isoniazid (INH) Inhibits mycolic acid synthesis in mycobacteria Ethambutol Inhibits incorporation of mycolic acid into the cell wall
36 The Inhibitors of Protein Synthesis 氯黴素 鏈黴素 四環黴素 Figure 20.4
37 Inhibitors of Protein Synthesis Chloramphenicol 氯黴素 Synthesized chemically; broad spectrum Binds 50S subunit, inhibits peptide bond formation Can suppress bone marrow and affect blood cell formation Figure 20.10
38 Aminoglycosides ( 胺基醣苷類 ): amino sugar is linked by glycoside bond Broad spectrum Changes shape of 30S subunit Can cause auditory damage Ex: streptomycin, neomycin, gentamycin, kanamycin 健大黴素
39 streptomycin neomycin gentamycin kanamycin
40 Tetracyclines 四環黴素 Broad spectrum Interferes with trna carrying the aa to the ribosome Figure Glycylcyclines 甘胺酰四環素類 New class of antibiotics since 2000, similar to tetracyclines Broad spectrum, useful against MRSA Binds 30S subunit, blocks protein synthesis
41 Macrolides 巨環類 Ex: erythromycin Narrow spectrum against Gram-positives Binds 50S, blocking the tunnel translocation Streptogramins 鏈陽性菌素 Against Gram-positives (vancomycinresistance) Binds 50S subunit, inhibits translation 紅黴素 Figure 20.12
42 Oxazolidinones 環氧酮類 New class of antibiotics developed in response to vacomycin resistance Against Gram-positives Binds 50S/30S subunit interface Pleuromutilins 截短側耳素 New class of antibiotics since 2000 Binds 50S, prevents translocation Ex: Retapamulin - topical and effective against gram-positives
43 Injury to the Plasma Membrane Affects synthesis of bacterial plasma membranes Lipopeptides ex: Ex: Daptomycin Produced by streptomycetes; used for skin infections Attacks the bacterial cell membrane Ex: polymyxin B Topical; bacteriocidal; effective against gram-negatives Combined with bacitracin and neomycin in nonprescription ointments
44 Nucleic Acid Synthesis Inhibitors This kind of drugs interfere the processes of DNA replication and transcription and have an extremely limited usefulness. Rifamycin (rifampin) Inhibits RNA synthesis Penetrates tissues; antitubercular activity Quinolones and fluoroquinolones Inhibits DNA gyrase
45 Competitive Inhibition of Essential Metabolites Sulfonamides (sulfa drugs) Inhibit the folic acid synthesis needed for nucleic acid and protein synthesis Competitively bind to the enzyme for PABA production, a folic acid precursor Combination of trimethoprim and sulfamethoxazole (TMP-SMZ) is an example of drug synergism
46 Figure Actions of the antibacterial synthetics trimethoprim and sulfamethoxazole. Synergism 協同作用 SMZ TMP 2016 Pearson Education, Ltd.
47 Antifungal Drugs Agents affecting fungal sterols: Interrupt the synthesis of ergosterol, making the membrane excessively permeable Polyenes Amphotericin B Azoles Miconazole Triazoles Allylamines
48 Agents affecting fungal walls Echinocandins Inhibit synthesis of -glucan. Agents inhibiting nucleic acids Flucytocine Cytosine analog interferes with RNA synthesis.
49 Other antifungal drugs: Griseofulvin: Produced by Penicillium; inhibits microtubule formation; active against superficial dermatophytes Tolnaftate: used for athlete's foot; action unknown. Pentamidine: Anti-Pneumocystis; maybe bind to DNA
50 Antiviral Drugs Entry and fusion inhibitors Block the receptors on the host cell that bind to the virus Block fusion of the virus and cell Uncoating, genome integration, and nucleic acid synthesis inhibitors Prevent viral uncoating Inhibit viral DNA integration into the host genome Nucleoside analogs inhibit RNA or DNA synthesis
51 Figure 20.16a The structure and function of the antiviral drug acyclovir Pearson Education, Ltd.
52 Figure 20.16b-c The structure and function of the antiviral drug acyclovir Pearson Education, Ltd.
53 Interference with assembly and release of viral particles Protease inhibitors: Block the cleavage of protein precursors Exit inhibitors Inhibit neuraminidase, an enzyme required for some viruses to bud from the host cell Interferons Produced by viral-infected cells to inhibit further spread of the infection Imiquimod: Promotes interferon production
54 Antivirals for Treating HIV/AIDS Antiretroviral: implies that a drug is used to treat HIV infections. Nucleoside analog (zidovudine) Nucleotide analog (tenofovir) Non-nucleoside inhibitors (nevirapine) Protease inhibitors (atazanavir) Integrase inhibitors (raltegravir) Entry inhibitors (miraviroc) Fusion inhibitors (enfuvirtide)
55 Antiprotozoan and antihelminthic Drugs Antiprotozoan drugs Quinine ( 奎寧, 金雞納霜 ), chloroquine: preventing malaria Artemisinin: Kills Plasmodium that causes malaria Metronidazole (Flagyl): damages DNA, also against anaerobic bacteria
56 Antihelminthic drugs Niclosamide: prevents ATP generation against tapeworms Praziquantel: alters membrane permeability against flatworms Mebendazole: inhibits nutrient absorption against intestinal roundworms Ivermectin: Paralyzes worm against intestinal roundworms
57 Tests to Guide Chemotherapy The Diffusion Methods Disk-diffusion method (Kirby-Bauer test): zone of inhibition Figure The disk-diffusion method for determining the activity of antimicrobials.
58 E test Determines the minimal inhibitory concentration (MIC) 最小抑菌濃度 Figure The E test (for epsilometer), a gradient diffusion method that determines antibiotic sensitivity and estimates minimal inhibitory concentration (MIC).
59 Broth Dilution Tests The diffusion methods doesn t determine whether a drug is bactericidal and not just bacteriostatic. Broth dilution test: Determine the MIC and MBC (minimal bactericidal concentration, 最小殺菌濃度 ) Test organism is placed into the wells of a tray containing dilutions of a drug; growth is determined Antibiograms: Reports that record the susceptibility of organisms encountered clinically
60 Figure A microdilution, or microtiter, plate used for testing for minimal inhibitory concentration (MIC) of antibiotics. Highest Concentration of drug on plates Lowest Doxycycline (White spots show growth in all wells; bacterium is resistant) Sulfamethoxazole (Trailing end point; usually read where there is an estimated 80% reduction in growth) Streptomycin (No growth in any well; bacterium is sensitive at all concentrations) Ethambutol (Growth in fourth wells; bacterium is equally sensitive to ethambutol and kanamycin) Kanamycin 2016 Pearson Education, Ltd.
61 Resistance to Antimicrobial Drugs Persister cells: microbes with genetic characteristics allowing for their survival when exposed to an antibiotic Superbugs: bacteria that are resistant to large numbers of antibiotics Resistance genes are often spread horizontally among bacteria on plasmids or transposons via conjugation or transduction
62 Mechanisms of Resistance A variety of mutations can lead to antibiotic resistance. Mechanisms of antibiotic resistance Enzymatic destruction or inactivation of drug Prevention of penetration to the target site within the microbe Alteration of drug's target site Rapid efflux (ejection) of the antibiotic Variations of mechanisms of resistance Resistance genes are often on plasmids or transposons that can be transferred between bacteria.
63 Figure Bacterial Resistance to Antibiotics. 1. Blocking entry Antibiotic 3. Alteration of target molecule Antibiotic Altered target molecule Antibiotic Enzymatic action 4. Efflux of antibiotic 2. Inactivation by enzymes Inactivated antibiotic KEY CONCEPTS There are only a few mechanisms of microbial resistance to antimicrobial agents: blocking the drug's entry into the cell, inactivation of the drug by enzymes, alteration of the drug's target site, efflux of the drug from the cell, or alteration of the metabolic pathways of the host. The mechanisms of bacterial resistance to antibiotics are limited. Knowledge of these mechanisms is critical for understanding the limitations of antibiotic use Pearson Education, Ltd.
64 Figure The development of an antibiotic-resistant mutant during antibiotic therapy. Initiation of antibiotic therapy Antibiotic resistance of bacterial population measured by amount of antibiotic needed to control growth Bacteria count 2016 Pearson Education, Ltd.
65 Antibiotic Misuse Misuse of antibiotics selects for resistance mutants. Misuse includes: Using outdated or weakened antibiotics. Using antibiotics for the common cold and other inappropriate conditions. Use of antibiotics in animal feed. Failure to complete the prescribed regimen. Using someone else's leftover prescription.
66
67 Effects of Combinations of Drugs Synergism occurs when the effect of two drugs together is greater than the effect of either alone. Figure An example of synergism between two different antibiotics. Antagonism occurs when the effect of two drugs together is less than the effect of either alone.
68 Future of Chemotherapeutic Agents Antimicrobial peptides Broad spectrum antibiotics from plants and animals Squalamine (sharks) Protegrin (pigs) Magainin (frogs) Phage therapy Bacteriocins: antimicrobial peptides produced by bacteria
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