M

ICRO

B

IOLOGY

Chapter 20

Antimicrobial Drugs

Dr. Abdelraouf A. Elmanama Ph. D Microbiology Medical Technology Department, Faculty of Science, Islamic University-Gaza

2008

Antimicrobial Drugs

• • • Chemotherapy • Antimicrobial drugs Antibiotic Selective toxicity The use of drugs to treat a disease Interfere with the growth of microbes within a host Substance produced by a microbe that, in small amounts, inhibits another microbe A drug that kills harmful microbes without damaging the host 2008

• • 1928 – Fleming discovered penicillin, produced by

Penicillium

.

1940 – Howard Florey and Ernst Chain performed first clinical trials of penicillin.

2008 Figure 20.1

2008 Table 20.1

2008 Table 20.2

The Action of Antimicrobial Drugs • • • • Broad-spectrum Superinfection Bactericidal Bacteriostatic 2008

2008 The Action of Antimicrobial Drugs Figure 20.2

2008 The Action of Antimicrobial Drugs Figure 20.4

Antibacterial Antibiotics Inhibitors of Cell Wall Synthesis • Penicillin • Natural penicillins • Semisynthetic penicillins 2008

Penicillins 2008 Figure 20.6

Antibacterial Antibiotics Inhibitors of Cell Wall Synthesis • Penicillin • Penicilinase-resistant penicillins • • • • Extended-spectrum penicillins Penicillins + Monobactam  Carbapenems -lactamase inhibitors 2008

2008 Antibacterial Antibiotics Inhibitors of Cell Wall Synthesis Figure 20.8

Antibacterial Antibiotics Inhibitors of Cell Wall Synthesis • Cephalosporins • 2 nd , 3 rd , and 4 th generations more effective against gram-negatives 2008 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

2008

Antibacterial Antibiotics Inhibitors of Cell Wall Synthesis • Antimycobacterium antibiotics • Isoniazid (INH) • Inhibits mycolic acid synthesis • Ethambutol • Inhibits incorporation of mycolic acid 2008

Antibacterial Antibiotics Inhibitors of Protein Synthesis • • Chloramphenicol • Broad spectrum • Binds 50S subunit, inhibits peptide bond formation Aminoglycosides • Streptomycin, neomycin, gentamycin • Broad spectrum • Changes shape of 30S subunit 2008

Antibacterial Antibiotics Inhibitors of Protein Synthesis • • • Tetracyclines • Broad spectrum • Interferes with tRNA attachment Macrolides • Gram-positives • Binds 50S, prevents translocation Erythromycin • Gram-positives • Binds 50S, prevents translocation 2008

Antibacterial Antibiotics Inhibitors of Protein Synthesis • • • Streptogramins • Gram-positives • Binds 50S subunit, inhibits translation Synercid • Gram-positives • Binds 50S subunit, inhibits translation Oxazolidinones • Linezolid • Gram-positives • Binds 50S subunit, prevents formation of 70S ribosome 2008

Antibacterial Antibiotics Injury to the Plasma Membrane • Polymyxin B • Topical • Combined with bacitracin and neomycin in over the-counter preparation 2008

Antibacterial Antibiotics Inhibitors of Nucleic Acid Synthesis • • Rifamycin • Inhibits RNA synthesis • Antituberculosis Quinolones and fluoroquinolones • • • Ciprofloxacin Inhibits DNA gyrase Urinary tract infections 2008

2008 Antibacterial Antibiotics Competitive Inhibitors • Sulfonamides (Sulfa drugs) • Inhibit folic acid synthesis • Broad spectrum Figure 5.7

2008 Figure 20.13

Antifungal Drugs Inhibition of Ergosterol Synthesis • • • Polyenes • Amphotericin B Azoles • Miconazole • Triazoles Allylamines 2008 Figure 20.15

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

Pneumocystis Candida

and 2008

Antifungal Drugs Inhibition of Nucleic Acids • • Flucytocine • Cytosine analog interferes with RNA synthesis Pentamidine isethionate • Anti-

Pneumocystis

; may bind DNA 2008

Antifungal Drugs Inhibition of Microtubules (Mitosis) • • Griseofulvin • Used for superficial mycoses Tolnaftate • Used for athlete's foot; action unknown 2008

2008 Antiviral Drugs Nucleoside and Nucleotide Analogs Figure 20.16a

2008 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 • Influenza Interferons prevent spread of viruses to new cells • Viral hepatitis 2008

Antiprotozoan Drugs • • • Chloroquine • Inhibits DNA synthesis • Malaria Diiodohydroxyquin • Unknown • Amoeba Metronidazole • Damages DNA • Entamoeba, Trichomonas 2008

Antihelminthic Drugs • • • Niclosamide • Prevents ATP generation • Tapeworms Praziquantel • Alters membrane permeability • Flatworms Pyantel pamoate • Neuromuscular block • Intestinal roundworms 2008

Antihelminthic Drugs • • Mebendazole • Inhibits nutrient absorption • Intestinal roundworms Ivermectin • Paralyzes worm • Intestinal roundworms 2008

Disk-Diffusion Test 2008 Figure 20.17

E Test 2008 Figure 20.18

• • MIC MBC Minimal inhibitory concentration Minimal bactericidal concentration 2008

Broth Dilution Test 2008 Figure 20.19

2008 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.

2008

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 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.

2008

2008 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 2008