Chapter 13

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: A 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 AntibioticsInhibitors of Cell Wall Synthesis

• Penicillin– Natural penicillins– Semisynthetic penicillins

Penicillins

Figure 20.6

Antibacterial AntibioticsInhibitors of Cell Wall Synthesis

• Penicillin– Penicilinase-resistant penicillins– Extended-spectrum penicillins– Penicillins + -lactamase inhibitors– Carbapenems– Monobactam

Antibacterial AntibioticsInhibitors of Cell Wall Synthesis

Figure 20.8

Antibacterial AntibioticsInhibitors of Cell Wall Synthesis

• Cephalosporins– 2nd, 3rd, and 4th

generations more effective against gram-negatives

Figure 20.9

Antibacterial AntibioticsInhibitors of Cell Wall Synthesis

• Polypeptide antibiotics– Bacitracin

• Topical application• Against gram-positives

– Vancomycin• Glycopeptide• Important "last line" against antibiotic resistant

S. aureus

Antibacterial AntibioticsInhibitors of Cell Wall Synthesis

• Antimycobacterial 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

• Broad spectrum– Changes shape of 30S subunit

Antibacterial AntibioticsInhibitors of Protein Synthesis

• Tetracyclines– Broad spectrum

• Interferes with tRNA attachment

• Streptogramins– Gram-positives

• Binds 50S subunit, inhibits translation

Figure 20.11

Antibacterial AntibioticsInhibitors of Protein Synthesis

• Macrolides

– Gram-positives

• Binds 50S, prevents

translocation

• Oxazolidinones

– Linezolid

• Gram-positives

– Binds 50S subunit, prevents

formation of 70S ribosomeFigure 20.12

Antibacterial AntibioticsInjury to the Plasma Membrane

• Polymyxin B– Topical– Combined with bacitracin and neomycin in

over-the-counter preparation.

Antibacterial AntibioticsInhibitors 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

• Influenza

• Interferons prevent spread of viruses to new cells

• Viral hepatitis

Figure 13.2b

Antiprotozoan Drugs• Chloroquine

– Inhibits DNA synthesis• Malaria

• Diiodohydroxyquin– Unknown

• Amoeba

• Metronidazole– Damages DNA

• Entamoeba, Trichomonas

Figure 12.17b

Antihelminthic Drugs• Niclosamide

– Prevents ATP generation• Tapeworms

• Praziquantel– Alters membrane

permeability• Flatworms

Figure 12.27

Antihelminthic Drugs• Mebendazole

– Inhibits nutrient absorption

• Intestinal roundworms

• Ivermectin– Paralyzes worm

• Intestinal roundworms

Figure 12.29a

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 resistance1. 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 or 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.