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PowerPoint to accompany Microbiology: A Systems Approach Cowan/Talaro Chapter 12 Drugs, Microbes, HostThe Elements of Chemotherapy Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Chapter 12 Topics - Antimicrobial Therapy - Selective Toxicity - Survey of Antimicrobial Drug - Microbial Drug Resistance - Drug and Host Interaction 2 Antimicrobial Therapy • Ideal drug • Terminology • Antibiotics 3 Important characteristics regarding antimicrobial drugs. Table 12.1 Characteristics of the ideal antimicrobial drug 4 Important terms related to chemotherapy. Table 12.2 Terminology of chemotherapy 5 Antibiotics • Naturally occurring antimicrobials – Metabolic products of bacteria and fungi – Reduce competition for nutrients and space • Bacteria – Streptomyces, Bacillus, • Molds – Penicillium, Cephalosporium 6 Selective Toxicity • Drugs that specifically target microbial processes, and not the human host cellular processes. 7 Selective Toxicity • • • • • • Mechanism of action Bacterial cell wall Nucleic acid synthesis Protein synthesis Cell membrane Folic acid synthesis 8 The mechanism of action for different antimicrobial drug targets in bacterial cells. Fig. 12.1 Primary sites of action of antimicrobial drugs on bacterial cells. 9 Cell wall synthesis • Bactericidal • Cycloserine – inhibits the formation of the basic peptidoglycan subunits • Vancomycin – hinders peptidoglycan elongation • Penicillin and cephalosporins – binds and blocks peptidases involved in cross-linking the glycan molecules 10 Antibiotics weaken the cell wall, and cause the cell to lyse. Fig. 12.2 The consequences of exposing a growing cell to antibiotics that prevent cell wall synthesis. 11 The mechanism of cell wall inhibition by penicillins and cephalosporins. Fig. 12.3 The mode of action of penicillins and cephalosporins 12 Nucleic acid synthesis • Chloroquine – binds and cross-links the double helix • Other quinolones – inhibits DNA unwinding enzymes • Viruses – Asidothymidine (AZT) – Analogs of purines and pyrimidines 13 Protein synthesis • Aminoglycosides – Binds the 30S ribosome – Misreads mRNA • Tetracyclines – Blocks attachment of tRNA • Chloramphenicol – Binds to the 50S ribosome – Prevents peptide bond formation 14 Examples of different antibiotics and their sites of inhibition on the procaryotic ribosome. Fig. 12.4 Sites of inhibition on the procaryotic ribosome and major antibiotic that act on these sites. 15 Cell membrane • Polymyxins – Interact with membrane phospholipids – Distorts the cell surface – Leakage of proteins and nitrogen bases • Anit-fungal – – – – Amphoterin B Forms complexes with sterols in the membrane Leakage Can affect human cell membranes (toxicity) 16 Folic acid synthesis • Sulfonamides (sulfa drug) and trimethoprim – Analogs – Competitive inhibition – Prevents the metabolism of DNA, RNA, and amino acid 17 Sulfonamides compete with PABA for the active site on the enzyme. 18 Fig. 12.5 The mode of action of sulfa drug. Survey of Antimicrobial Drugs • • • • • • • Penicillin Cephalosporins Streptomycin Tetracyline Sulfomides Polyenes Antiviral 19 Important chemotherapeutic agents used to treat infectious diseases. Table 12.3 Selected survey o chemotherapeutic agents in infectious diseases. 20 Important chemotherapeutic agents used to treat infectious diseases. Table 12.3 Selected survey o chemotherapeutic agents in infectious diseases. 21 Important chemotherapeutic agents used to treat infectious diseases. Table 12.3 Selected survey o chemotherapeutic agents in infectious diseases. 22 Penicillin • Penicillin chrysogenum • A diverse group (1st, 2nd , 3rd generations) – Natural (penicillin G and V) – Semisynthetic (ampicillin) • Structure – Thiazolidine ring – Beta-lactam ring – Variable side chain (R group) 23 Penicillin continued • Resistance – if bacteria contain penicillinases • Inhibits cell wall synthesis • Treat streptococci, meningococci, and spirochete infections 24 The R group is responsible for the activity of the drug, and cleavage of the beta-lactam ring will render the drug inactive. Fig. 12.6 Chemical structure of penicillins 25 Cephalosporin • Cephalosporium acremonium (mold) • Widely administered today – Diverse group (natural and semisynthetic) • Structure – similar to penicillin except • Main ring is different • Two sites for R groups 26 Cephalosporin continued • Resistant to most pencillinases • Broad-spectrum – inhibits cell wall synthesis • 3rd generation drugs used to treat enteric bacteria, respiratory, skin, urinary and nervous system infections 27 The different R groups allow for versatility and improved effectiveness. Fig. 12.7 The structure of cephalosporins 28 Aminoglycosides • Streptomyces and Micromonospora • Structure – Amino sugars and an aminocyclitol ring • Broad-spectrum • Commonly used to treat bubonic plague and sexually transmitted diseases • Inhibits protein synthesis 29 The amino sugars and six-carbon ring (aminocyclitol) are characteristics associated with streptomycin. Fig. 12.8 The structure of streptomycin 30 Streptomyces synthesizes many different antibiotics such as aminoglycosides, tetracycline, chloramphenicol, and erythromycin. Fig. 12.9 A colony of Streptomyces 31 Tetracycline • Streptomyces • Structure – – Diverse – complex series of rings • Broad spectrum and low cost • Commonly used to treat sexually transmitted diseases • Side effects – gastrointestinal disruption • Inhibits proteins synthesis 32 Chloramphenicol • • • • • • • Streptomyces Structure - nitrobenzene structure Broad-spectrum Only made synthetically today Treat typhoid fever, brain abscesses Side effects – aplastic anemia Inhibits protein synthesis 33 Erythromycin • • • • Streptomyces Structure – macrolide ring Broad-spectrum Commonly used as prophylactic drug prior to surgery • Side effects - low toxicity • Inhibits protein synthesis 34 Comparison of three broad-spectrum antibiotics tetracycline, chloramphenicol, and erythromycin. Fig. 12.10 Structures of three broad-spectrum antibiotics 35 Sulfonamides (sulfa drugs) • Synthetic drug • Based on sulfanilamides • Used in combination with other synthetics such as trimethoprim • Commonly used to treat pneumonia in AIDS patients • Inhibits folic acid synthesis 36 Attachment of different R groups to the main structural nucleus enables versatility of sulfonamides. Fig. 12.11 The structures of some sulfonamides 37 Polyenes • Antifungal • Structure – large complex steroidal structure • Some toxicity to humans • Commonly used for skin infections • Targets the membrane - lost of selective permeability 38 Comparison of different antifungal drug structures, which include polyenes, azoles, and flucytosine. Fig. 12.12 Some antifungal drug structures 39 Other types of antimicrobials • Antiprotozoan – metronidazole – Treat giardia • Antimalarial – Quinine – malaria • Antihelminthic – mebendazole – Tapeworms, roundworms 40 Antiviral • Limited drugs available • Difficult to maintain selective toxicity • Effective drugs – target viral replication cycle – Entry – Nucleic acid synthesis – Assembly/release • Interferon – artificial antiviral drug 41 Antiviral drug structures and their mode of action. Table 12.5 Actions of selected antiviral drugs. 42 Antiviral drug structures and their mode of action. Table 12.5 Actions of selected antiviral drugs. 43 Antiviral drug structures and their mode of action. Table 12.5 Actions of selected antiviral drugs. 44 Antimicrobial Resistance • • • • • • • Resistance factors New enzymes Permeability Alter receptors Change metabolic patterns Natural selection New approaches 45 Intermicrobial transfer of plasmids containing resistance genes (R factors) occurs by conjugation, transformation,and transduction. Fig. 12.13 Spread of resistance factors 46 Different mechanisms that are commonly associated with drug resistance. Fig. 12.14 Examples of mechanisms of acquired drug resistance 47 Demonstration of how natural selection enables resistant strains to become dominant. Fig. 12.15 The events in natural selection for drug resistance 48 New approaches • Increase drug resistance requires new approaches for developing effective antimicrobials – Prevent iron –scavenging capabilities – Inhibit genetic controls (riboswitches) – Probiotics and prebiotics 49 Drug and Host Interaction • • • • Toxicity to organs Allergic reactions Suppress/alter microflora Effective drugs 50 Tetracycline treatments can cause teeth discoloration. Fig. 12.16 Drug-induced side effect. 51 Disrupting the microflora in the intestine can result in superinfections. Fig. 12.17 The role of antimicrobials in disrupting microbial Flora 52 Summary of antimicrobial drugs, the primary tissues affected, and the damage produced. Table 12.6 Major adverse toxic reactions to common drug groups. 53 Effective drugs • Identify infectious agent • Sensitivity testing • Minimum Inhibitory Concentration (MIC) 54 Sensitivity test such as the Kirby-Bauer Test can be used to determine the effectiveness of a drug by measuring the zone of inhibition. Table 12.7 Results of a sample kirby-bauer test 55 An example of the Kirby-Bauer Test. Fig. 12.18 Technique for preparation and interpretation of disc diffusion test. 56 The E-test is an alternative to the Kirby-Bauer procedure. Fig. 12.19 Alternative to the Kirby-Bauer 57 The dilution test is an effective method of determining the MIC. Fig. 12.20 Tube dilution test for determining the MIC 58 The lower the MIC, the more effective the drug is toward combating the bacterium. Table 12.8 Comparative MICs 59