Mechanisms of Action Antifungal Drugs

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Mechanisms of Action Antifungal Drugs
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Interference with Membrane Integrity

• Polyenes
• Attaches to ergosterol ? disrupts cell membrane ?
  cell lysis
• Some toxicity to humans due to binding of
  cholesterol
• ex amphotericin B
• Azoles
• Inhibition of ergosterol synthesis ? disrupts
  cell membrane ? cell lysis
• ex miconazole, ketoconazole

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Disruption of Cytoplasmic Membranes
Figure 10.5
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Mechanisms of Action Antiparasitic Drugs

• Antiparasitic drugs often very specific ? ID
  organism
• Antiprotozoan drugs
• interfere with biosynthetic pathways
  sulfonamides, trimethoprim
• Heavy metals, quinines, azoles
• Antihelminthic drugs
• interfere with neuromuscular function
  praziquantel
• Niclosamide, azoles
• Most diseases are in developing world - need more
  !

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Spectrum of Action
Figure 10.8
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Antimicrobial Efficacy

• Tests used to determine susceptibility of a
  bacterial strain to a specific antibiotic
• MIC
• MBC
• Antibiotic discs

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Minimum inhibitory concentration (MIC)

• Serial dilutions of concentrations of drug
• Add known concentration of organisms
• Incubate gt16 hrs
• Examine for turbidity
• Minimum bacteriocidal concentration (MBC)
  lowest concentration of a specific antimicrobial
  drug that kills 99.9 of a given strain of
  bacteria
• Must assay for live organisms from MIC test
• MIC and MBC precise but labor-intensive and
  expensive

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Minimum inhibitory concentration lowest
concentration that inhibits growth
Figure 10.10
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Minimum Bactericidal Concentration (MBC) Test
Figure 10.12
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Kirby-Bauer Test Antibiotic Disc Diffusion

• Bacterial lawn plated on agar
• Filter paper discs with specific concentration of
  drug on bacterial surface
• Clear area surrounding disc zone of inhibition
  around disc

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Etest
Figure 10.11
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Resistance to Antimicrobial Drugs

• How does resistance arise?
• How does resistance spread?

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Antimicrobial Resistance

• Innate/ intrinsic resistance inherent
  resistance
• Acquired resistance previously sensitive
  organisms develop resistance

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Mechanisms of Resistance
Non-Resistant Cell

• Antibiotic Resistance
• Drug-inactivating enzymes
• Alteration in target molecule
• Decreased drug uptake
• Increased drug elimination

Resistant Cell
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Drug-Inactivating Enzymes

• ?-lactamase (penicillinase) renders penicillin
  inactive

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Alteration in the Target Molecule

• Alteration in the ribosome ? inhibits binding of
  erythromycin

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Decreased Drug Uptake

• Some cells have mutated to decrease uptake of
  tetracycline

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Increased Drug Elimination

• Efflux pumps proteins present in cell membrane
  that expels substances out of the cell
• E. coli resistance to triclosan

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Antimicrobial Resistance!
R plasmids resistance plasmids Multiple
Resistance R plasmids can carry resistance to
multiple antimicrobials Superbugs resistance to
most antimicrobial agents Cross resistance
resistance to one antimicrobial confers
resistance to another

• Horizontal evolution through gene transfer

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Emerging Antimicrobial Resistance

• Staphylococcus aureus
• Common, nosocomial infections
• Most strains contain penicillinase
• MRSA methicillin-resistant S. aureus
• Enterococcus (faecium or faecalis)
• Common, nosocomial infections
• VRE vancomycin-resistance enterococcus
• Mycobacterium tuberculosis
• Slow growth ? treatment is long
• High number of organisms in active infection ?
  high probability of spontaneous mutation ?
  complicated treatment
• MDR-TB multi-drug resistant tuberculosis

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CDC Campaign to Prevent Resistance in
Healthcare Settings

• http//www.cdc.gov/drugresistance/healthcare/defau
  lt.htm

• Limiting Antibiotic Resistance
• Completing the entire course of antibiotics
• Use antibiotics in combination
• Limit use to necessary cases
• Develope new variants of existing drugs

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Strategies for New Antibiotics

• Modifying current antibiotics
• Utilizing mechanisms of resistance when modifying
  current antibiotics
• Identifying/ inhibiting new antibiotic targets
• Bacteriophage viruses that only infect bacteria
• Use enzymes from phage
• 5. Strengthen/ imitate normal immune system
  funciton
• 6. Exploration of environmental sources (marine,
  soil)

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Some New Antibiotics

• Quinupristin-Dalfopristin FDA approved 1999
• Useful against Gram()
• Class streptogramins (lincosamidemacrolide)
• Linezolid FDA approved 2000
• Useful against Gram() and Gram(-)
• Class oxazolidinones
• Daptomycin FDA approved 2003
• Useful against Gram() only
• Causes depolarization of cell membrane
• New class of antibiotics
• Telithromycin FDA approved 2004
• Useful against Gram() only
• Inhibits activity of large ribosomal subunit
• Class ketolides / macrolides

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Why isnt there more development?

• Big pharmaceutical companies
• Smaller () market for anti-infectives
• Combinatorial chemistry and genomics have not
  delivered easy drugs/ drug targets
• Years to complete process

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