Drugs, Microbes, Host The Elements of Chemotherapy

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Drugs, Microbes, Host The Elements of
Chemotherapy

• Antibiotics - Still Miracle Drugs

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Paul Ehrlichs Magic Bullets
Salvarsan No. 606
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Fleming and Penicillin
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Antibiotics

• Topics
• - Antimicrobial Therapy
• - Selective Toxicity
• - Survey of Antimicrobial Drugs
• - Microbial Drug Resistance
• - Drug and Host Interaction

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Antibiotics

• Naturally occurring antimicrobials
• Metabolic products of bacteria and fungi
• Reduce competition for nutrients and space
• Bacteria that produce them
• Streptomyces, Bacillus,
• Molds
• Penicillium, Cephalosporium

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Selective Toxicity

• Drugs that specifically target microbial
  processes, and not the human host cellular
  processes.

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Selective ToxicityMechanisms and sites

• Mechanism of action
• Bacterial cell wall
• Nucleic acid synthesis
• Protein synthesis
• Cell membrane
• Folic acid synthesis

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Cell wall synthesis

• Bactericidal
• Penicillin and cephalosporins binds and blocks
  peptidases involved in cross-linking the glycan
  molecules
• Vancomycin hinders peptidoglycan elongation
• Cycloserine inhibits the formation of the basic
  peptidoglycan subunits

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Antibiotics weaken the cell wall, and cause
the cell to lyse.
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The mechanism of action of penicillins and
cephalosporins.
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Penicillin

• Penicillin chrysogenum
• A diverse group (1st, 2nd , 3rd generations)
• Natural (penicillin G and V)
• Semisynthetic (Ampicillin, Carbenicillin)
• Structure
• Thiazolidine ring
• Beta-lactam ring
• Variable side chain (R group)

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The R group is responsible for the activity of
the drug, and cleavage of the beta-lactam ring
will render the drug inactive.
Chemical structure of penicillins
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Penicillinase (b Lactamase)
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Cephalosporin

• Cephalosporium acremonium (mold)
• Widely administered today
• Diverse group (natural and semisynthetic)
• 1st, 2nd, and 3rd generations
• Structure
• similar to penicillin except
• Main ring is different
• Two sites for R groups

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The different R groups allow for versatility and
improved effectiveness.
The structure of cephalosporins
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Inhibition of Protein synthesis

• Aminoglycosides
• Bind to the 30S ribosome
• Causes Misreading of mRNA
• Tetracyclines
• Block attachment of tRNA
• Chloramphenicol
• Binds to the 50S ribosome
• Prevents peptide bond formation

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Inhibitors of Protein Synthesis

• Broad spectrum, toxicity problems
• Examples
• Aminoglycosides Streptomycin, neomycin,
  gentamycin
• Tetracyclines
• Macrolides Erythromycin
• Chloramphenicol

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Aminoglycosides

• From Streptomyces
• Inhibit protein synthesis

Streptomyces synthesizes many different
antibiotics such as aminoglycosides,
tetracycline, chloramphenicol, and erythromycin.
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Tetracycline

• Inhibits proteins synthesis
• Broad spectrum and low cost
• Commonly used to treat sexually transmitted
  diseases
• Minor side effect gastrointestinal disruption

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Erythromycin

• Inhibits protein synthesis
• Broad-spectrum
• Commonly used as prophylactic drug prior to
  surgery
• Side effects - low toxicity

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Chloramphenicol

• Inhibits protein synthesis
• Broad-spectrum
• Treat typhoid fever, brain abscesses
• Rarely used now due to side effects aplastic
  anemia

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Aminoglycoside
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Sites of inhibition on the procaryotic ribosome
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Injury to the Plasma Membrane

• Polymyxin B (Gram negatives)
• Topical
• Combined with bacitracin and neomycin (broad
  spectrum) in over-the-counter preparation

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Inhibitors of Nucleic Acid Synthesis

• Rifamycin
• Inhibits RNA synthesis
• Antituberculosis
• Quinolones and fluoroquinolones
• Ciprofloxacin
• Inhibits DNA gyrase
• Urinary tract infections

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Folic acid synthesis

• Sulfonamides (sulfa drug) and trimethoprim
• Analogs
• Competitive inhibition of enzymes
• Prevents the metabolism of DNA, RNA, and amino
  acid

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Sulfonamides compete with PABA for the active
site on the enzyme.
The sulfonamide Sulfamethoxazole is commonly used
in combination with trimethoprim
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Antiviral

• Increasing types of drugs becoming available
• However, it is difficult to maintain selective
  toxicity
• Effective drugs target viral replication cycle
• Entry
• Nucleic acid synthesis
• Assembly/release
• Interferon genetically engineered antiviral
  protein from a human gene

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Antiviral drug structures and their unique modes
of action.
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Antiviral drug structures and their unique modes
of action.
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Antiviral drug structures and their uniquemodes
of action.
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Other types of antimicrobials

• Antifungal ketoconizole
• Antiprotozoan metronidazole
• Treat giardia
• Antimalarial Quinine
• malaria
• Antihelminthic mebendazole
• Tapeworms, roundworms

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Mechanisms of Antibiotic Resistance

• Enzymatic destruction of drug
• Prevention of penetration of drug
• Alteration of drug's target site
• Rapid ejection of the drug

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Antimicrobial Resistance

• Relative or complete lack of effect of
  antimicrobial against a previously susceptible
  microbe

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Antibiotic Resistance
Figure 20.20
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Antibiotic Resistance
Intermicrobial transfer of plasmids containing
resistance genes (R factors) occurs by
conjugation, transformation,and transduction
Figure 20.20
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What Factors Promote Antimicrobial Resistance?

• Exposure to sub-optimal levels of antimicrobial
• Inappropriate use
• Exposure to microbes carrying resistance genes

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Inappropriate Antimicrobial Use

• Prescription not taken correctly
• Antibiotics for viral infections
• Antibiotics sold without
• medical supervision
• Spread of resistant microbes
• in hospitals due to lack of hygiene

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Inappropriate Antimicrobial Use

• Inadequate surveillance or defective
  susceptibility assays
• Poverty or war
• Use of antibiotics in foods
• Lack of quality control in manufacture or
  outdated antimicrobial

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Antibiotics in Foods

• Antibiotics are used in animal feeds and sprayed
  on plants to prevent infection and promote growth
• Multi drug-resistant Salmonella typhi has been
  found in 4 states in 18 people who ate beef fed
  antibiotics

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Antibiotic Drug and Host Interaction

• Toxicity to organs
• Allergic reactions
• Suppress/alter microflora
• Effective drugs

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Tetracycline treatments can cause teeth
discoloration.
Disrupting the normal flora in the intestine can
result in superinfections.
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Finding an effective drug for trreatment

• Identify infectious agent
• Perform sensitivity testing
• Often the Minimum Inhibitory Concentration (MIC)
  is determined

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The Kirby-Bauer Test.
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Sensitivity test such as the Kirby-Bauer Test can
be used to determine the effectiveness of a drug
by measuring the zone of inhibition.
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Consequences of Antimicrobial Resistance

• Infections resistant to available antibiotics
• Increased cost of treatment

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Multi-Drug Resistant TB
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Proposals to Combat Antimicrobial Resistance

• Speed development of new antibiotics
• Track resistance data nationwide
• Restrict antimicrobial use
• Direct observed dosing (TB)

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Proposals to Combat Antimicrobial Resistance

• Use more narrow spectrum antibiotics
• Use antimicrobial cocktails

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The Future of Chemotherapeutic Agents

• Antimicrobial peptides
• Broad spectrum antibiotics from plants and
  animals
• Squalamine (sharks)
• Protegrin (pigs)
• Magainin (frogs)

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The Future of Chemotherapeutic Agents

• Antisense agents
• Complementary DNA or peptide nucleic acids that
  binds to a pathogen's virulence gene(s) and
  prevents transcription