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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
• 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
Definitions
• Chemotherapy
• Antimicrobial drugs
• Antibiotic
• Selective toxicity
• Bacteriostatic/
bacteriocidal
• Spectrum of activity
between
narrow vs.
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
Modes of action that either kill or
inhibit growth
Range of effect within or
groups of microbes;
broad-spectrum
Table 20.2
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
The Action of Antimicrobial Drugs
Figure 20.2
Protein Synthesis Inhibitors
Figure 20.4
The Action of Antimicrobial Drugs
Figure 20.2
Antibacterial Antibiotics
Inhibitors of Cell Wall Synthesis: Penicilins
• Penicillins
• Natural penicillins: G, V
• Semisynthetic penicillins
• “-cillin “ suffix
• Carbapenems
• Monobactam
Penicillins
Figure 20.6
Antibacterial Antibiotics
Inhibitors of Cell Wall Synthesis:Cephalosporins
• Cephalosporins
• 2nd, 3rd, and 4th
generations more
effective against
gram-negatives
Figure 20.9
Antibacterial Antibiotics
Inhibitors of Cell Wall Synthesis: Polypeptides
• 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: Anti-Mycobacterials
• Antimycobacterium antibiotics
• Isoniazid (INH)
• Inhibits mycolic acid synthesis
• Ethambutol
• Inhibits incorporation of mycolic acid
The Action of Antimicrobial Drugs
Figure 20.2
Antibacterial Antibiotics
Injury to the Plasma Membrane
• Polymyxin B
• Topical
• Combined with bacitracin and neomycin in overthe-counter preparation
The Action of Antimicrobial Drugs
Figure 20.2
Antibacterial Antibiotics
Inhibitors of Nucleic Acid Synthesis
• Rifamycin
• Inhibits RNA synthesis by RNA polymerase
• Antituberculosis
• Quinolones and fluoroquinolones
• Ciprofloxacin
• Inhibits DNA gyrase so blocks DNA polymerase
• Urinary tract infections
The Action of Antimicrobial Drugs
Figure 20.2
Antibacterial Antibiotics
Competitive Inhibitors
• Sulfonamides (Sulfa drugs)
• Inhibit folic acid synthesis
• Broad spectrum
Figure 5.7
TMZ - Trimethoprim + Sulfamethoxazole: Synergism
Figure 20.13
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
Antifungal Drugs
Damage through Ergosterol
• Leakage thorough
binding ergosterol
• Amphotericin B
• Inibitors of Ergosterol
Syntehsis
• Miconazole,
fluconazole
• Triazoles
Antifungal Drugs
Inhibition of Cell Wall Synthesis
• Echinocandins
• Inhibit synthesis of glucan
• Cancidas is used
against Candida and
Pneumocystis
Other Antifungal Drugs
• 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
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
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
• Inhibits attachment
• Zanamivir
• Influenza
• Inhibits uncoating
• Amantadine
• Influenza
• Interferons prevent spread of viruses to new cells
• Viral hepatitis
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
Antiprotozoan Drugs
• 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)
Antihelminthic Drugs
• 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
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
Population becomes increasingly resistant
Bacteria Populations Under Sub-Lethal Selection Pressure Evolve to Become More Resistant
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.
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.
• 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
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
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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