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Antimicrobial Drugs Chemotherapy: the use of drugs to treat a disease Antimicrobial drugs: interfere with the growth of microbes within a host Antibiotic: a substance produced by a microbe that, in small amounts, inhibits another microbe Selective toxicity: killing harmful microbes without damaging the host Antimicrobial Drugs 1928: Fleming discovered penicillin, produced by Penicillium 1940: Howard Florey and Ernst Chain performed first clinical trials of penicillin Figure 20.1 Laboratory observation of antibiosis. Table 20.1 Representative Sources of Antibiotics Insert Table 20.1 The Spectrum of Antimicrobial Activity Broad spectrum Narrow spectrum Superinfection Table 20.2 The Spectrum of Activity of Antibiotics and Other Antimicrobial Drugs The Action of Antimicrobial Drugs Bactericidal Kill microbes directly Bacteriostatic Prevent microbes from growing Figure 20.3 The inhibition of bacterial cell synthesis by penicillin. Rod-shaped bacterium before penicillin. The bacterial cell lysing as penicillin weakens the cell wall. Figure 20.4 The inhibition of protein synthesis by antibiotics. Protein synthesis site Growing polypeptide Tunnel Growing polypeptide 50S 5′ Chloramphenicol Binds to 50S portion and inhibits formation of peptide bond 30S mRNA 50S portion 3′ Three-dimensional detail of the protein synthesis site showing the 30S and 50S subunit portions of the 70S prokaryotic ribosome Messenger RNA Streptomycin Changes shape of 30S portion, causing code on mRNA to be read incorrectly Protein synthesis site tRNA 30S portion Direction of ribosome movement Tetracyclines 70S prokaryotic ribosome Translation Interfere with attachment of tRNA to mRNA–ribosome complex Diagram indicating the different points at which chloramphenicol, the tetracyclines, and streptomycin exert their activities Figure 20.5 Injury to the plasma membrane of a yeast cell caused by an antifungal drug. Table 20.3 Antibacterial Drugs (Part 1 of 3) Table 20.3 Antibacterial Drugs (Part 2 of 3) Table 20.3 Antibacterial Drugs (Part 3 of 3) Figure 20.2 Major Action Modes of Antimicrobial Drugs. 1. Inhibition of cell wall synthesis: penicillins, 2. Inhibition of protein synthesis: chloramphenicol, cephalosporins, bacitracin, vancomycin erythryomycin, tetracyclines, streptomycin DNA mRNA Transcription Protein Translation Replication Enzyme 4. Injury to plasma membrane: polymyxin B 5. Inhibition of essential metabolite synthesis: sulfanimide, trimethoprim 3. Inhibition of nucleic acid replication and transcription: quinolones, rifampin Tests to Guide Chemotherapy MIC: minimal inhibitory concentration MBC: minimal bactericidal concentration Antibiogram Figure 20.17 The disk-diffusion method for determining the activity of antimicrobials. Figure 20.18 The E test (for epsilometer), a gradient diffusion method that determines antibiotic sensitivity and estimates minimal inhibitory concentration (MIC). MIC MIC Figure 20.19 A microdilution, or microtiter, plate used for testing for minimal inhibitory concentration (MIC) of antibiotics. Doxycycline (Growth in all wells, resistant) Sulfamethoxazole (Trailing end point; usually read where there is an estimated 80% reduction in growth) Streptomycin (No growth in any well; sensitive at all concentrations) Ethambutol (Growth in fourth wells; equally sensitive to ethambutol and kanamycin) Kanamycin Decreasing concentration of drug Figure 20.21 The development of an antibiotic-resistant mutant during antibiotic therapy. Bacteria (number/ml) Initiation of antibiotic therapy 108 50 107 40 106 30 Bacteria count 105 20 104 10 103 0 1 2 3 4 5 6 Days 7 8 9 10 11 Antibiotic resistance (mg/ml) Antibiotic resistance of bacterial population measured by amount of antibiotic needed to control growth Antibiotic Resistance A variety of mutations can lead to antibiotic resistance Resistance genes are often on plasmids or transposons that can be transferred between bacteria Antibiotic Resistance Misuse of antibiotics selects for resistance mutants Misuse includes: Using outdated or weakened antibiotics Using antibiotics for the common cold and other inappropriate conditions Using antibiotics in animal feed Failing to complete the prescribed regimen Using someone else’s leftover prescription Figure 20.20 Bacterial Resistance to Antibiotics. 1. Blocking entry Antibiotic 2. Inactivation by enzymes Antibiotic Antibiotic Altered target molecule Enzymatic action 3. Alteration of target molecule 4. Efflux of antibiotic Inactivated antibiotic Resistance plasmid S. enterica after conjugation S. enterica Cephalosporin-resistance in E. coli transferred by conjugation to Salmonella enterica in the intestinal tracts of turkeys. E. coli Clinical Focus Antibiotics in Animal Feed Linked to Human Disease, Figure A. Clinical Focus Antibiotics in Animal Feed Linked to Human Disease, Figure B. Flouroquinolone-resistant Campylobacter jejuni in the United States, 1986–2008. Percent FQ-resistant Campylobacter 30 FQ for humans FQ for poultry FQ for poultry discontinued 25 20 15 10 5 0 1986 1988 1990 1992 1994 1996 1998 Year 2000 2002 2004 2006 2008 Effects of Combinations of Drugs Synergism occurs when the effect of two drugs together is greater than the effect of either alone Antagonism occurs when the effect of two drugs together is less than the effect of either alone Figure 20.23 An example of synergism between two different antibiotics. Area of synergistic inhibition, clear Disk with antibiotic amoxicillin-clavulanic acid Area of growth, cloudy Disk with antibiotic aztreonam