Chapter 20 Antimicrobial Drugs

Antimicrobial Drugs Chemotherapy The use of drugs to treat a disease Antimicrobial drugs Interfere with the growth of microbes within a host Antibiotic Substance produced by a microbe that, in small amounts, inhibits another microbe Selective toxicity A drug that kills harmful microbes without damaging the host

1928 – Fleming discovered penicillin, produced by Penicillium. 1940 – Howard Florey and Ernst Chain performed first clinical trials of penicillin. Figure 20.1

Table 20.1

Table 20.2

The Action of Antimicrobial Drugs Broad-spectrum Superinfection Bactericidal Bacteriostatic

The Action of Antimicrobial Drugs Figure 20.2

The Action of Antimicrobial Drugs Figure 20.4

Antibacterial Antibiotics Inhibitors of Cell Wall Synthesis Penicillin Natural penicillins Semisynthetic penicillins

Penicillins Figure 20.6

Antibacterial Antibiotics Inhibitors of Cell Wall Synthesis Penicillin Penicilinase-resistant penicillins Extended-spectrum penicillins Penicillins + -lactamase inhibitors Carbapenems Monobactam

Antibacterial Antibiotics Inhibitors of Cell Wall Synthesis Figure 20.8

Antibacterial Antibiotics Inhibitors of Cell Wall Synthesis Cephalosporins 2nd, 3rd, and 4th generations more effective against gram-negatives Figure 20.9

Antibacterial Antibiotics Inhibitors of Cell Wall Synthesis Polypeptide antibiotics Bacitracin Topical application Against gram-positives Vancomycin Glycopeptide Important "last line" against antibiotic resistant S. aureus

Antibacterial Antibiotics Inhibitors of Cell Wall Synthesis Antimycobacterium antibiotics Isoniazid (INH) Inhibits mycolic acid synthesis Ethambutol Inhibits incorporation of mycolic acid

Antibacterial Antibiotics Inhibitors of Protein Synthesis Chloramphenicol Broad spectrum Binds 50S subunit, inhibits peptide bond formation Aminoglycosides Streptomycin, neomycin, gentamycin Changes shape of 30S subunit

Antibacterial Antibiotics Inhibitors of Protein Synthesis Tetracyclines Broad spectrum Interferes with tRNA attachment Macrolides Gram-positives Binds 50S, prevents translocation Erythromycin

Antibacterial Antibiotics Inhibitors of Protein Synthesis Streptogramins Gram-positives Binds 50S subunit, inhibits translation Synercid Oxazolidinones Linezolid Binds 50S subunit, prevents formation of 70S ribosome

Antibacterial Antibiotics Injury to the Plasma Membrane Polymyxin B Topical Combined with bacitracin and neomycin in over-the-counter preparation

Antibacterial Antibiotics Inhibitors of Nucleic Acid Synthesis Rifamycin Inhibits RNA synthesis Antituberculosis Quinolones and fluoroquinolones Ciprofloxacin Inhibits DNA gyrase Urinary tract infections

Antibacterial Antibiotics Competitive Inhibitors Sulfonamides (Sulfa drugs) Inhibit folic acid synthesis Broad spectrum Figure 5.7

Figure 20.13

Antifungal Drugs Inhibition of Ergosterol Synthesis Polyenes Amphotericin B Azoles Miconazole Triazoles Allylamines Figure 20.15

Antifungal Drugs Inhibition of Cell Wall Synthesis Echinocandins Inhibit synthesis of -glucan Cancidas is used against Candida and Pneumocystis

Antifungal Drugs Inhibition of Nucleic Acids Flucytocine Cytosine analog interferes with RNA synthesis Pentamidine isethionate Anti-Pneumocystis; may bind DNA

Antifungal Drugs Inhibition of Microtubules (Mitosis) Griseofulvin Used for superficial mycoses Tolnaftate Used for athlete's foot; action unknown

Antiviral Drugs Nucleoside and Nucleotide Analogs Figure 20.16a

Antiviral Drugs Nucleoside and Nucleotide Analogs Figure 20.16b, c

Antiviral Drugs Enzyme Inhibitors Protease inhibitors Indinavir HIV Inhibit attachment Zanamivir Influenza Inhibit uncoating Amantadine Interferons prevent spread of viruses to new cells Viral hepatitis

Antiprotozoan Drugs Chloroquine Inhibits DNA synthesis Malaria Diiodohydroxyquin Unknown Amoeba Metronidazole Damages DNA Entamoeba, Trichomonas

Antihelminthic Drugs Niclosamide Prevents ATP generation Tapeworms Praziquantel Alters membrane permeability Flatworms Pyantel pamoate Neuromuscular block Intestinal roundworms

Antihelminthic Drugs Mebendazole Inhibits nutrient absorption Intestinal roundworms Ivermectin Paralyzes worm

Disk-Diffusion Test Figure 20.17

E Test Figure 20.18

MIC Minimal inhibitory concentration MBC Minimal bactericidal concentration

Broth Dilution Test Figure 20.19

Figure 20.20

Antibiotic Resistance A variety of mutations can lead to antibiotic resistance. Mechanisms of antibiotic resistance 1. Enzymatic destruction of drug 2. Prevention of penetration of drug 3. Alteration of drug's target site 4. Rapid ejection of the drug 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, 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

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.

Effects of Combinations of Drugs Figure 20.22

The Future of Chemotherapeutic Agents Antimicrobial peptides Broad spectrum antibiotics from plants and animals Squalamine (sharks) Protegrin (pigs) Magainin (frogs) Antisense agents Complementary DNA or peptide nucleic acids that binds to a pathogen's virulence gene(s) and prevents transcription