Antimicrobial Drugs Overview • by MikeJenny


									Antimicrobial Drugs
•   I. Introduction
•   II. Mechanism of Action
•   III. Evaluation of Antimicrobials
•   IV. Development of Resistance
•   V. Future Chemotherapeutic Agents
            I. Introduction

• Drugs: chemicals that affect physiology in
  any manner
• Chemotherapeutic agents – drugs that act
  against diseases
• Antimicrobial agents – drugs that treat
        Ideal Antimicrobial Agent

•   Readily available
•   Inexpensive
•   Chemically stable
•   Easily administered
•   Nontoxic and nonallergenic
•   Selectively toxic to infective agent
•   Broad spectrum
II. Mechanisms of Antimicrobial
• Key is selective toxicity
• Antibacterial drugs>>anti-eukaryotic
  drugs>>>>>>antiviral drugs
Mechanisms of Antimicrobial Action
A. Inhibition of Cell Wall Synthesis
Inhibition of Cell Wall Synthesis
Inhibition of Cell Wall Synthesis

Beta-lactams bind to enzymes that cross-link NAM
 Inhibition of Cell Wall Synthesis

• Semisynthetic derivatives of beta-lactams
  – More stable in acidic environments
  – More readily absorbed
  – Less susceptible to deactivation
  – More active against more types of bacteria
• Simplest beta-lactams – effective only
  against aerobic Gram-negatives
 Inhibition of Cell Wall Synthesis

• Vancomycin and cycloserine: interfere with
  particular alanine-alanine bridges that link
  NAM subunits in many Gram-positives
• Bacitracin: blocks secretion of NAG and
  NAM from cytoplasm
B. Inhibition of Protein Synthesis
• Prokaryotic ribosomes are 70S (30S and
• Eukaryotic ribosomes are 80S (40S and
• Drugs can selectively target translation
• Mitochondria of animals and humans
  contain 70S ribosomes; can be harmful
Protein Synthesis Inhibition
   C. Disruption of Cytoplasmic
• Some drugs incorporate into cytoplasmic
  membranes and damage integrity
• Amphotericin B (polyene) attaches to
  ergosterol found in fungal membranes
  – Humans somewhat susceptible, cholesterol
    similar to ergosterol
  – Bacteria lack sterols; not susceptible
• Polymyxin disrupts cytoplasmic membranes
  of Gram-negatives; toxic to human kidneys
Disrupting Cytoplasmic Membranes
     D. Inhibition of Metabolic
• Effective when differences exist between
  metabolic processes of pathogen and host
• Heavy metals inactivate enzymes
• Agents that rid body of parasitic worms by
  paralyzing them
• Drugs block activation of viruses
• Metabolic antagonists
Inhibition of Metabolic Pathways
Folic Acid Inhibition
                    folic acid
                    from our
   E. Inhibition of Nucleic Acid
• Block DNA replication or mRNA transcription
• Only slight differences between prokaryotic
  and eukaryotic DNA; drugs often affect both
  types of cells
• Not normally used to treat infections
• Used in research and perhaps to slow
  cancer cell replication
      Inhibition of Nucleic Acid
• Nucleotide analogs: distort shapes of
  nucleic acid molecules
  – prevents further replication, transcription, or
• Most often used against viruses
  – viral DNA polymerases more likely to
    incorporate analogs
  – viral nucleic acid synthesis more rapid than that
    in host cells
• Also effective against rapidly dividing cancer
Inhibition of Nucleic Acid Synthesis
     Inhibition of Nucleic Acid
• Quinolones and fluoroquinolones: act
  against prokaryotic DNA gyrase
• Rufampin: binds to and inhibits action of
  RNA polymerase during transcription
       F. Prevention of Virus
• Attachment can be blocked
  – peptide and sugar analogs of receptor
    proteins (attachment antagonists)
• Still in developmental stage
  III. Evaluation of Antimicrobial

• Spectrum of action
• Efficacy
  – Dosages required to be effective
  – Routes of administration
  – Overall safety
• Side effects
Spectrum of Action
         Spectrum of Action

• Broad-spectrum antimicrobials:
  – may allow for secondary or superinfections to
  – Killing of normal flora reduces microbial

• Ascertained by
  – Diffusion susceptibility tests
  – Minimum inhibitory concentration test
  – Minimum bactericidal concentration test
Diffusion Susceptibility Test
Minimum Inhibitory Concentration
          (MIC) Test
Minimum Inhibitory Concentration
          (MIC) Test
Minimum Bactericidal Concentration
          (MBC) Test
Routes of Immunization
       Routes of Immunization
• Topical application if infection is external
• Oral – simplest; lower drug concentrations;
  no reliance on health care provider; patients
  do not always follow prescribing information
• Intramuscular – requires needle for
  administration; concentration never as high
  as IV administration
• Intravenous – requires needle or catheter;
  drug concentration diminishes as liver and
  kidneys remove drug from circulation
• Must know how antimicrobial agent will be
  distributed to infected tissues
      Safety and Side Effects

• Three main categories of side effects
  – Toxicity
  – Allergies
  – Disruption of normal microbiota

• Cause of many adverse reactions poorly
• Drugs may be toxic to kidneys, liver, or
• Considerations needed when prescribing
  drugs to pregnant women

• Although allergic reactions are rare, they
  may be life threatening
• Anaphylactic shock
Disruption of Normal Microbiota

• May result in secondary infections
• Overgrowth of normal flora –
• Of greatest concern for hospitalized
IV. The Development of Resistant
    Organisms in Populations
• Some are naturally partially or completely
• Resistance by bacteria acquired in 2 ways
  – New mutations of chromosomal genes
  – Acquisition of R-plasmids via transformation,
    transduction, and conjugation
       Methods of Resistance
• 1. Destruction or Inactivation of drug
  – Beta-lactamase
• 2. Prevention of penetration to target site
  within the microbe
  – Tetracycline resistance
• 3. Alteration of the drug’s target sites
  – AA change in ribosomes
• 4. Rapid efflux-MDR pumps
The Development of Resistant
  Organisms in Populations
  Multiple Resistance and Cross
• Pathogen can acquire resistance to more
  than one drug at a time
• Common when R-plasmids exchanged, or
• Develop in hospitals and nursing homes;
  constant use of drugs eliminates sensitive
• Superbugs
• Cross resistance
• CDC reports inappropriate use of
  antibiotics in US:
  – 30% for ear infections
  – 100% for common cold
  – 50% for sore throat
• More than half of the 100,000 tons
  consumed annually are used in animal
  feeds to decrease infections and increase
  Animal Feeds and Antibiotics
• Linked to human diseases
• Constant use creates a selective pressure
  for resistance
  – Salmonella: can be transferred to humans via
    milk and meat
    • 1985: 16,000 people in 7 states infected with
      antibiotic-resistant S. typhimurium from one Illinois
    • 1985: 1,000 cases of infection by S. newport
      resistant to multiple antibiotics in LA
  Animal Feeds and Antibiotics
• Enterococcus:
  – Vancomycin resistance found in US in 1989
• Campylobacter: found in poultry intestines
  – Fluoroquinolone antibiotics used to prevent
  – 1990: FQ-resistant C. jejuni found in humans,
    linked to grocery-store purchased chicken
  – Now banned
   Prevention Dietary Illnesses
• Use competitive exclusion, rather than
  – Prevent colonization in farm animals
• Decrease fecal contamination during
  processing at slaughterhouses
• Proper cooking and storage
Retarding Resistance in Humans:
• Need:
  – Maintenance of high concentrations of drug
  – Interval of treatment needs to kill sensitive cells
    and inhibit others long enough for immune
    system to destroy
• Use antimicrobial agents in combination
• Limit use of unnecessary antimicrobials
• Development of new variations of existing
  drugs (novel side chains added to original
  – Second-generation drugs
  – Third-generation drugs
    V. Future Chemotherapeutic
• Antimicrobial peptides that form channels
  in PM
• Antisense agents that bind and block
  microbial DNA that codes for pathogenicity
• Bacteriophage products
•   I. Introduction
•   II. Mechanism of Action
•   III. Evaluation of Antimicrobials
•   IV. Development of Resistance
•   V. Future Chemotherapeutic Agents

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