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Antimicrobial Drugs • History • Some definitions • Mechanisms of Action or Antibacterials • Protein synthesis inhibitors • Cell wall synthesis inhibitors • Plasma membrane-injuring agents • Nucleic acid inhibitors • Metabolic/enzyme inhibitors • Antifungals • Antivirals • Antiprotozoan drugs • Antihelminthics • Antibiotic Resistance

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Page 1: Antimicrobial Drugs History Some definitions Mechanisms of Action or Antibacterials Protein synthesis inhibitors Cell wall synthesis inhibitors Plasma

Antimicrobial Drugs

• History

• Some definitions

• Mechanisms of Action or Antibacterials

• Protein synthesis inhibitors

• Cell wall synthesis inhibitors

• Plasma membrane-injuring agents

• Nucleic acid inhibitors

• Metabolic/enzyme inhibitors

• Antifungals

• Antivirals

• Antiprotozoan drugs

• Antihelminthics

• Antibiotic Resistance

Page 2: Antimicrobial Drugs History Some definitions Mechanisms of Action or Antibacterials Protein synthesis inhibitors Cell wall synthesis inhibitors Plasma

• 1928 – Fleming discovered penicillin, produced by Penicillium.

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

Figure 20.1

Page 3: Antimicrobial Drugs History Some definitions Mechanisms of Action or Antibacterials Protein synthesis inhibitors Cell wall synthesis inhibitors Plasma

Table 20.1

Page 4: Antimicrobial Drugs History Some definitions Mechanisms of Action or Antibacterials Protein synthesis inhibitors Cell wall synthesis inhibitors Plasma

Definitions• 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

• Bacteriostatic/ Modes of action that either kill or

bacteriocidal inhibit growth• Spectrum of activity Range of effect within or

between groups of microbes; narrow vs. broad-spectrum

Page 5: Antimicrobial Drugs History Some definitions Mechanisms of Action or Antibacterials Protein synthesis inhibitors Cell wall synthesis inhibitors Plasma

Table 20.2

Page 6: Antimicrobial Drugs History Some definitions Mechanisms of Action or Antibacterials Protein synthesis inhibitors Cell wall synthesis inhibitors Plasma

Antimicrobial Drugs

• History

• Some definitions

• Mechanisms of Action of Antibacterials

• Protein synthesis inhibitors

• Cell wall synthesis inhibitors

• Plasma membrane-injuring agents

• Nucleic acid inhibitors

• Metabolic/enzyme inhibitors

• Antifungals

• Antivirals

• Antiprotozoan drugs

• Antihelminthics

• Antibiotic Resistance

Page 7: Antimicrobial Drugs History Some definitions Mechanisms of Action or Antibacterials Protein synthesis inhibitors Cell wall synthesis inhibitors Plasma

The Action of Antimicrobial Drugs

Figure 20.2

Page 8: Antimicrobial Drugs History Some definitions Mechanisms of Action or Antibacterials Protein synthesis inhibitors Cell wall synthesis inhibitors Plasma

Protein Synthesis Inhibitors

Figure 20.4

Page 9: Antimicrobial Drugs History Some definitions Mechanisms of Action or Antibacterials Protein synthesis inhibitors Cell wall synthesis inhibitors Plasma

The Action of Antimicrobial Drugs

Figure 20.2

Page 10: Antimicrobial Drugs History Some definitions Mechanisms of Action or Antibacterials Protein synthesis inhibitors Cell wall synthesis inhibitors Plasma

• Penicillins

• Natural penicillins: G, V

• Semisynthetic penicillins

• “-cillin “ suffix

• Carbapenems

• Monobactam

Antibacterial Antibiotics Inhibitors of Cell Wall Synthesis: Penicilins

Page 11: Antimicrobial Drugs History Some definitions Mechanisms of Action or Antibacterials Protein synthesis inhibitors Cell wall synthesis inhibitors Plasma

Penicillins

Figure 20.6

Page 12: Antimicrobial Drugs History Some definitions Mechanisms of Action or Antibacterials Protein synthesis inhibitors Cell wall synthesis inhibitors Plasma

• Cephalosporins

• 2nd, 3rd, and 4th generations more effective against gram-negatives

Antibacterial Antibiotics Inhibitors of Cell Wall Synthesis:Cephalosporins

Figure 20.9

Page 13: Antimicrobial Drugs History Some definitions Mechanisms of Action or Antibacterials Protein synthesis inhibitors Cell wall synthesis inhibitors Plasma

• Polypeptide antibiotics

• Bacitracin

• Topical application

• Against gram-positives

• Vancomycin

• Glycopeptide

• Important "last line" against antibiotic resistant S. aureus (e.g. MRSA)

Antibacterial Antibiotics Inhibitors of Cell Wall Synthesis: Polypeptides

Page 14: Antimicrobial Drugs History Some definitions Mechanisms of Action or Antibacterials Protein synthesis inhibitors Cell wall synthesis inhibitors Plasma

• Antimycobacterium antibiotics

• Isoniazid (INH)

• Inhibits mycolic acid synthesis

• Ethambutol

• Inhibits incorporation of mycolic acid

Antibacterial Antibiotics Inhibitors of Cell Wall Synthesis: Anti-Mycobacterials

Page 15: Antimicrobial Drugs History Some definitions Mechanisms of Action or Antibacterials Protein synthesis inhibitors Cell wall synthesis inhibitors Plasma

The Action of Antimicrobial Drugs

Figure 20.2

Page 16: Antimicrobial Drugs History Some definitions Mechanisms of Action or Antibacterials Protein synthesis inhibitors Cell wall synthesis inhibitors Plasma

• Polymyxin B

• Topical

• Combined with bacitracin and neomycin in over-the-counter preparation

Antibacterial Antibiotics Injury to the Plasma Membrane

Page 17: Antimicrobial Drugs History Some definitions Mechanisms of Action or Antibacterials Protein synthesis inhibitors Cell wall synthesis inhibitors Plasma

The Action of Antimicrobial Drugs

Figure 20.2

Page 18: Antimicrobial Drugs History Some definitions Mechanisms of Action or Antibacterials Protein synthesis inhibitors Cell wall synthesis inhibitors Plasma

• Rifamycin

• Inhibits RNA synthesis by RNA polymerase

• Antituberculosis

• Quinolones and fluoroquinolones

• Ciprofloxacin

• Inhibits DNA gyrase so blocks DNA polymerase

• Urinary tract infections

Antibacterial Antibiotics Inhibitors of Nucleic Acid Synthesis

Page 19: Antimicrobial Drugs History Some definitions Mechanisms of Action or Antibacterials Protein synthesis inhibitors Cell wall synthesis inhibitors Plasma

The Action of Antimicrobial Drugs

Figure 20.2

Page 20: Antimicrobial Drugs History Some definitions Mechanisms of Action or Antibacterials Protein synthesis inhibitors Cell wall synthesis inhibitors Plasma

• Sulfonamides (Sulfa drugs)

• Inhibit folic acid synthesis

• Broad spectrum

Antibacterial Antibiotics Competitive Inhibitors

Figure 5.7

Page 21: Antimicrobial Drugs History Some definitions Mechanisms of Action or Antibacterials Protein synthesis inhibitors Cell wall synthesis inhibitors Plasma

Figure 20.13

TMZ - Trimethoprim + Sulfamethoxazole: Synergism

Page 22: Antimicrobial Drugs History Some definitions Mechanisms of Action or Antibacterials Protein synthesis inhibitors Cell wall synthesis inhibitors Plasma

Antimicrobial Drugs

• History

• Some definitions

• Mechanisms of Action or Antibacterials

• Protein synthesis inhibitors

• Cell wall synthesis inhibitors

• Plasma membrane-injuring agents

• Nucleic acid inhibitors

• Metabolic/enzyme inhibitors

• Antifungals

• Antivirals

• Antiprotozoan drugs

• Antihelminthics

• Antibiotic Resistance

Page 23: Antimicrobial Drugs History Some definitions Mechanisms of Action or Antibacterials Protein synthesis inhibitors Cell wall synthesis inhibitors Plasma

• Leakage thorough binding ergosterol

• Amphotericin B

• Inibitors of Ergosterol Syntehsis

• Miconazole, fluconazole

• Triazoles

Antifungal DrugsDamage through Ergosterol

Page 24: Antimicrobial Drugs History Some definitions Mechanisms of Action or Antibacterials Protein synthesis inhibitors Cell wall synthesis inhibitors Plasma

• Echinocandins

• Inhibit synthesis of -glucan

• Cancidas is used against Candida and Pneumocystis

Antifungal DrugsInhibition of Cell Wall Synthesis

Page 25: Antimicrobial Drugs History Some definitions Mechanisms of Action or Antibacterials Protein synthesis inhibitors Cell wall synthesis inhibitors Plasma

• Inhibition of Nucleic Acids • Flucytocine: cytosine analog interferes with RNA

synthesis• Pentamidine isethionate for Pneumocytis : binds to

DNA

• Inhibition of Mitosis (microtubule beakers)• Griseofulvin

• Used for superficial mycoses• Tolnaftate

• Used for athlete's foot; action unknown

Other Antifungal Drugs

Page 26: Antimicrobial Drugs History Some definitions Mechanisms of Action or Antibacterials Protein synthesis inhibitors Cell wall synthesis inhibitors Plasma

Antimicrobial Drugs

• History

• Some definitions

• Mechanisms of Action or Antibacterials

• Protein synthesis inhibitors

• Cell wall synthesis inhibitors

• Plasma membrane-injuring agents

• Nucleic acid inhibitors

• Metabolic/enzyme inhibitors

• Antifungals

• Antivirals

• Antiprotozoan drugs

• Antihelminthics

• Antibiotic Resistance

Page 27: Antimicrobial Drugs History Some definitions Mechanisms of Action or Antibacterials Protein synthesis inhibitors Cell wall synthesis inhibitors Plasma

Antiviral DrugsNucleoside and Nucleotide Analogs

Figure 20.16a

Page 28: Antimicrobial Drugs History Some definitions Mechanisms of Action or Antibacterials Protein synthesis inhibitors Cell wall synthesis inhibitors Plasma

Antiviral DrugsNucleoside and Nucleotide Analogs

Figure 20.16b, c

Page 29: Antimicrobial Drugs History Some definitions Mechanisms of Action or Antibacterials Protein synthesis inhibitors Cell wall synthesis inhibitors Plasma

• Protease inhibitors• Indinavir

• HIV• Inhibits attachment

• Zanamivir• Influenza

• Inhibits uncoating• Amantadine

• Influenza• Interferons prevent spread of viruses to new cells

• Viral hepatitis

Antiviral DrugsEnzyme Inhibitors

Page 30: Antimicrobial Drugs History Some definitions Mechanisms of Action or Antibacterials Protein synthesis inhibitors Cell wall synthesis inhibitors Plasma

Antimicrobial Drugs

• History

• Some definitions

• Mechanisms of Action or Antibacterials

• Protein synthesis inhibitors

• Cell wall synthesis inhibitors

• Plasma membrane-injuring agents

• Nucleic acid inhibitors

• Metabolic/enzyme inhibitors

• Antifungals

• Antivirals

• Antiprotozoan drugs

• Antihelminthics

• Antibiotic Resistance

Page 31: Antimicrobial Drugs History Some definitions Mechanisms of Action or Antibacterials Protein synthesis inhibitors Cell wall synthesis inhibitors Plasma

• Chloroquine

• Inhibits DNA synthesis

• Malaria

• Diiodohydroxyquin

• Unknown

• Amoeba

• Metronidazole (Flagyl)

• Damages DNA after becoming toxic from fermentation enzymes

• Entamoeba, Trichomonas, Giardia (no mitochondria!)

• (also works on obligately anaerobic bacteria like Clostrdium)

Antiprotozoan Drugs

Page 32: Antimicrobial Drugs History Some definitions Mechanisms of Action or Antibacterials Protein synthesis inhibitors Cell wall synthesis inhibitors Plasma

• Niclosamide

• Prevents ATP generation

• Tapeworms

• Praziquantel

• Alters membrane permeability

• Flatworms

• Pyantel pamoate

• Neuromuscular block

• Intestinal roundworms

• Mebendazole

• Inhibits nutrient absorption

• Intestinal roundworms

• Ivermectin

• Paralyzes worm

• Intestinal roundworms

Antihelminthic Drugs

Page 33: Antimicrobial Drugs History Some definitions Mechanisms of Action or Antibacterials Protein synthesis inhibitors Cell wall synthesis inhibitors Plasma

Antimicrobial Drugs

• History

• Some definitions

• Mechanisms of Action or Antibacterials

• Protein synthesis inhibitors

• Cell wall synthesis inhibitors

• Plasma membrane-injuring agents

• Nucleic acid inhibitors

• Metabolic/enzyme inhibitors

• Antifungals

• Antivirals

• Antiprotozoan drugs

• Antihelminthics

• Antibiotic Resistance: Natural Selection

Page 34: Antimicrobial Drugs History Some definitions Mechanisms of Action or Antibacterials Protein synthesis inhibitors Cell wall synthesis inhibitors Plasma

Bacteria Populations Under Sub-Lethal Selection Pressure Evolve to Become More ResistantP

opu

lati

on b

ecom

es in

crea

sin

gly

resi

stan

t

1. Every bacterial population has variations in resistance due to gene transfer among them and mutation. Resistance is coded by DNA.

2. Some variants survive a brief antibiotic challenge because of their resistance.

3. Survivors are the “parents” of the next generation and pass on their particular resistance genes in their DNA.

4. The next and subsequent generations are composed of many variants. As a whole, the population is more resistant than the last.

Page 35: Antimicrobial Drugs History Some definitions Mechanisms of Action or Antibacterials Protein synthesis inhibitors Cell wall synthesis inhibitors Plasma

• 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

Page 36: Antimicrobial Drugs History Some definitions Mechanisms of Action or Antibacterials Protein synthesis inhibitors Cell wall synthesis inhibitors Plasma

• 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

Antibiotic Resistance

Page 37: Antimicrobial Drugs History Some definitions Mechanisms of Action or Antibacterials Protein synthesis inhibitors Cell wall synthesis inhibitors Plasma

• Synergism occurs when the effect of two drugs together is greater than the effect of either alone.

• E.g. Sulfamethoxazole and trimethoprim

• Penicillin with beta-lactamase inhibitor (clav. acid)

• Alcohol and sleeping pills

• Antagonism occurs when the effect of two drugs together is less than the effect of either alone.

• E.g. Ibuprofen (anti-diuretic properties) + diuretic

• Penicillin + streptomycin

Effects of Combinations of Drugs

Page 38: Antimicrobial Drugs History Some definitions Mechanisms of Action or Antibacterials Protein synthesis inhibitors Cell wall synthesis inhibitors Plasma

• 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

The Future of Chemotherapeutic Agents

Page 39: Antimicrobial Drugs History Some definitions Mechanisms of Action or Antibacterials Protein synthesis inhibitors Cell wall synthesis inhibitors Plasma

Antimicrobial Drugs

• History

• Some definitions

• Mechanisms of Action or Antibacterials

• Protein synthesis inhibitors

• Cell wall synthesis inhibitors

• Plasma membrane-injuring agents

• Nucleic acid inhibitors

• Metabolic/enzyme inhibitors

• Antifungals

• Antivirals

• Antiprotozoan drugs

• Antihelminthics

• Antibiotic Resistance


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