Antimicrobial Drugs Chemotherapy the use of drugs to

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 50 S 5′ Chloramphenicol Binds to 50 S portion and inhibits formation of peptide bond 30 S m. RNA 50 S portion 3′ Three-dimensional detail of the protein synthesis site showing the 30 S and 50 S subunit portions of the 70 S prokaryotic ribosome Messenger RNA Streptomycin Changes shape of 30 S portion, causing code on m. RNA to be read incorrectly Protein synthesis site t. RNA 30 S portion 70 S prokaryotic ribosome Translation Direction of ribosome movement Tetracyclines Interfere with attachment of t. RNA to m. RNA–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 m. RNA 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

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 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 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