Antimicrobial Drugs

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Lecture 11

• Antimicrobial Drugs

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Antimicrobial Drugs

• Chemicals used to treat microbial infections
• Before antimicrobials, large number of people
  died from common illnesses
• Now many illnesses easily treated with
  antimicrobials
• However, many antimicrobial drugs are becoming
  less useful

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Antimicrobial Drugs

• Chemotherapeutic agent
• Antimicrobial drug
• Different types of antimicrobial drugs
• Antibacterial drugs
• Antifungal drugs
• Antiprotozoan drugs
• Antihelminthic drugs

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Paul Ehrlich

• He observed that certain dyes stain bacterial
  cells and not animal cells
• Theorized that there could be a dye or chemical
  that would harm bacterial cells but not human
  cells
• Systematic search for chemical to cure syphilis
• 606th compound tested proved to be highly
  effective in treating laboratory animals

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Gerhard Domagk

• Discovered red dye, Prontosil effective in
  treating Streococcal infections in animals
• No effect in test tubes
• Enzymes in animals blood split Prontosil molecule
  into sulfanilamide- this acted against
  streptococcal
• Sulfa Drug

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Alexander Fleming

• Working on cultures of Staphylococcus
• Contamination with mold
• Noticed colonies growing near mold looked odd
• Found that mold was secreting substance that was
  killing bacteria

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Figure 20.1
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Features of Antimicrobial Drugs

• Most modern antibiotics come from species of
  microorganisms that live in the soil
• To commercially produce antibiotic
• Select strain and grow in broth
• When maximum antibiotic concentration reached,
  extract from medium
• Purify
• Chemical alter to make it more stable

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Features of Antimicrobial Drugs Selective
Toxicity

• Cause greater harm to microorganisms than to host
• Chemotherapeutic index lowest dose toxic to
  patient divided by dose typically used for therapy

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Features of Antimicrobial Drugs Antimicrobial
Action

• Bacteriostatic inhibit growth of microorganisms
• Bactericidal Kill microorganisms

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Features of Antimicrobial DrugsSpectrum of
Activity

• Antimicrobial medications vary with respect to
  the range of microorganisms they kill or inhibit
• Some kill only limited range Narrow-spectrum
  antimicrobial
• While others kill wide range of microorganisms
  Broad-spectrum antimicrobial

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Features of Antimicrobial DrugsEffects of
Combining Drugs

• Combinations are sometimes used to fight
  infections
• Synergistic action of one drug enhances the
  activity of another
• Antagonistic activity of one drug interferes
  with the action of another

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Features of Antimicrobial DrugsAdverse Effects

• Allergic Reactions some people develop
  hypersensitivities to antimicrobials
• Toxic Effects some antimicrobials toxic at high
  concentrations or cause adverse effects
• Suppression of normal flora when normal flora
  killed, other pathogens may be able to grow to
  high numbers

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Features of Antimicrobial DrugsResistance to
Antimicrobials

• Some microorganisms inherently resistant to
  effects of a particular drug
• Other previously sensitive microorganisms can
  develop resistance through spontaneous mutations
  or acquisition of new genes

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Mechanisms of action of Antibacterial Drugs

• Inhibit cell wall synthesis
• Inhibit protein synthesis
• Inhibit nucleic acid synthesis
• Injury to plasma membrane
• Inhibit synthesis of essential metabolites

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Figure 20.2
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b-Lactam Drugs- inhibit cell wall synthesis

• Irreversibly inhibit enzymes involved in the
  final steps of cell wall synthesis
• These enzymes mediate formation of peptide
  bridges between adjacent stands of peptidoglycan
• b-lactam ring similar in structure to normal
  substrate of enzyme
• Drug binds to enzyme, competitively inhibit
  enzymatic activity

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b-Lactam Drugs

• Some bacteria produce b-lactamase- enzyme that
  breaks the critical b-lactam ring
• b-lactam drugs include penicillins and
  cephalosporins

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Antibacterial medications that inhibit protein
synthesis

• Target ribosomes of bacteria
• Aminoglycosides bind to 30S subunit causing it
  to distort and malfunction blocks initiation of
  translation
• Tetracyclines bind to 30S subunit blocking
  attachment of tRNA
• Macrolides bind 50S subunit and prevents
  continuation of protein synthesis

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Figure 20.4b
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Antibacterial medications that inhibit nucleic
acid synthesis

• Target enzymes required for nucleic acid
  synthesis
• Fluoroquinolones inhibit enzymes that maintain
  the supercoiling of closed circular DNA
• Rifamycins block prokaryotic RNA polymerase from
  initiating transcription

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Antibacterial medications injure plasma membrane

• Polymyxin B binds to membrane of G- bacteria and
  alters permeability
• This leads to leakage of cellular contents and
  cell death
• These drugs also bind to eukaryotic cells to some
  extent, which limits their use to topical
  applications

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Antibacterial drugs that inhibit synthesis of
essential metabolites

• Competitive inhibition by substance that
  resembles normal substrate of enzyme
• Sulfa drugs

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Antiviral Drugs

• Very few antiviral drugs approved for use in US
• Effective against a very limited group of
  diseases
• Targets for antiviral drugs are various points of
  viral reproduction

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Nucleoside and Nucleotide analogs

• Acyclovir- used to treat genital herpes
• Cidofovir- used for treatment of cytomegaloviral
  infections of the eye
• Lamivudine- used to treat Hepatitus B

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Antiretrovirals

• Currently implies, a drug used to treat HIV
• Tenofovir- nucleotide reverse transcriptase
  inhibitor
• Zidovudine- nucleoside analog

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Other enzyme inhibitors

• Zanamivir (Relenza) and Oseltamivir phosphate
  (Tamiflu)- inhibitors of the enzyme neuominidase
• Used to treat influenza
• Indinavir- protease inhibitors

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Interferons

• Cells infected by a virus often produce
  interferon, which inhibits further spread of the
  infection
• Alpha-interferon- drug for treatment of viral
  hepatitis infections

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Antifungal drugs

• More difficult to find point of selective
  toxicity in eukaryotes than in prokaryotes
• Targets of antifungal drugs
• Agents affecting fungal sterols
• Agents affecting fungal cell walls
• Agents inhibiting nucleic acids

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Agents affecting fungal sterols

• Many antifungals target the sterols in the plasma
  membrane
• Polyenes- used in systemic fungal infections,
  very toxic to kidneys
• Azoles- used for athletes foot and vaginal yeast
  infections (miconizole)

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Agents affecting fungal cell walls

• primary target of selective toxicity is ß-glucan
• Inhibition of synthesis of this glucan results in
  an incomplete cell wall, and results in lysis of
  the cell
• Caspofungin- first new class of antifungals in 40
  years

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Agents inhibiting nucleic acids

• Flucytin- nucleotide analog of cytosine,
  interferes with the biosynthesis of RNA, and
  therefore protein synthesis

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Antiprotozoan drugs

• Quinine still used to control malaria
• Chloroquinone- synthetic derivative has largely
  replaced it
• Mefloquinone- used in areas where resistance to
  chloroquinone has developed
• Quinacrine- drug of choice for treating protozoan
  disease, giardiasis

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Antihelminthic drugs

• Praziquantel- used in treatment of tapeworms
  kills worms by altering permeability of plasma
  membranes

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Kirby-Bauer method for determining drug
susceptibility

• Bacteria spread on surface of agar plate
• 12 disks, each with different antimicrobial drug,
  placed on agar plate
• Incubated- drugs diffuse outward and kill
  susceptible bacteria
• Zone of inhibition around each disk
• Compare size of zone to chart

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Figure 21.10
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Resistance to antimicrobial drugs

• Drug resistance limits use of ALL known
  antimicrobials
• Penicillin G first introduced, only 3 of
  bacteria resistant
• Now, over 90 are resistant

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How do bacteria become resistant?

• Spontaneous Mutation happen as cells replicate
• Gene Transfer Usually spread through conjugative
  transfer of R plasmid

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Slowing the emergence and spread of antimicrobial
resistance

• Responsibilities of Physicians must work to
  identify microbe and prescribe suitable
  antimicrobials, must educate patients
• Responsibilities of Patients need to carefully
  follow instructions

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Slowing the emergence and spread of antimicrobial
resistance

• 3. Educate Public must understand
  appropriateness and limitations of antibiotics
  antibiotics not effective against viruses
• 4. Global Impacts organism that is resistant can
  quickly travel to another country
• - in some countries antibiotics available on
  non-prescription basis
• - antibiotics fed to animals can select for
  drug- resistant organisms

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New Approaches to Antibiotic Therapy Are Needed

• Scientists work to find new antibiotic targets in
  pathogens
• Discovery of new and unique antibiotics is
  necessary