Antimicrobial Drugs

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Antimicrobial Drugs

• Fading Miracle?

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Ehrlichs Magic Bullets
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Fleming and Penicillin
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Chemotherapy

• The use of drugs to treat a disease
• Selective toxicity A drug that kills harmful
  microbes without damaging the host

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Antibiotic/Antimicrobial

• Antibiotic Chemical produced by a microorganism
  that kills or inhibits the growth of another
  microorganism
• Antimicrobial agent Chemical that kills or
  inhibits the growth of microorganisms

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Microbial Sources of Antibiotics
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Antibiotic Spectrum of Activity

• No antibiotic is effective against all microbes

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Mechanisms of Antimicrobial Action

• Bacteria have their own enzymes for
• Cell wall formation
• Protein synthesis
• DNA replication
• RNA synthesis
• Synthesis of essential metabolites

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Mechanisms of Antimicrobial Action

• Viruses use host enzymes inside host cells
• Fungi and protozoa have own eukaryotic enzymes
• The more similar the pathogen and host enzymes,
  the more side effects the antimicrobials will have

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Modes of Antimicrobial Action
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Antibacterial Antibiotics Inhibitors of Cell
Wall Synthesis

• Penicillin (over 50 compounds)
• Share 4-sided ring (b lactam ring)
• Natural penicillins
• Narrow range of action
• Susceptible to penicillinase (b lactamase)

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Prokaryotic Cell Walls
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PenicillinsFig 20.6
Figure 20.6
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Penicillinase (b Lactamase)
Figure 20.8
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Semisynthetic Penicillins

• Penicilinase-resistant penicillins
• Carbapenems very broad spectrum
• Monobactam Gram negative
• Extended-spectrum penicillins
• Penicillins ?-lactamase inhibitors

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Other Inhibitors of Cell Wall Synthesis

• Cephalosporins
• 2nd, 3rd, and 4th generations more effective
  against gram-negatives

Figure 20.9
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Other Inhibitors of Cell Wall Synthesis

• Polypeptide antibiotics
• Bacitracin
• Topical application
• Against gram-positives
• Vancomycin
• Glycopeptide
• Important "last line" against antibiotic
  resistant S. aureus

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Other Inhibitors of Cell Wall Synthesis

• Antibiotics effective against Mycobacteria
  interfere with mycolic acid synthesis or
  incorporation
• Isoniazid (INH)
• Ethambutol

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Inhibitors of Protein Synthesis

• Broad spectrum, toxicity problems
• Examples
• Chloramphenicol (bone marrow)
• Aminoglycosides Streptomycin, neomycin,
  gentamycin (hearing, kidneys)
• Tetracyclines (Rickettsias Chlamydia GI tract)
• Macrolides Erythromycin (gram , used in
  children)

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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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Competitive Inhibitors

• Sulfonamides (Sulfa drugs)
• Inhibit folic acid synthesis
• Broad spectrum

Figure 5.7
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Antifungal Drugs

• Fungi are eukaryotes
• Have unique sterols in their cell walls
• Pathogenic fungi are often outside the body

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Antiviral Drugs

• Viruses are composed of nucleic acid, protein
  capsid, and host membrane containing virus
  proteins
• Viruses live inside host cells and use many host
  enzymes
• Some viruses have unique enzymes for DNA/RNA
  synthesis or protein cutting in virus assembly

Figure 20.16a
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Antiviral DrugsNucleoside and Nucleotide Analogs
Figure 20.16a
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Analogs Block DNA Synthesis
Figure 20.16b, c
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Antiviral DrugsEnzyme Inhibitors

• Inhibit assembly
• Indinavir (HIV)
• Inhibit attachment
• Zanamivir (Influenza)
• Inhibit uncoating
• Amantadine (Influenza)

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Antiviral DrugsEnzyme Inhibitors

• Interferons prevent spread of viruses to new
  cells (Viral hepatitis)
• Natural products of the immune system in viral
  infections

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Antiprotozoan Drugs

• Protozoa are eukaryotic cells
• Many drugs are experimental and their mode of
  action is unknown

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Antihelminthic Drugs

• Helminths are macroscopic multicellular
  eukaryotic organisms tapeworms, roundworms,
  pinworms, hookworms

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Antihelminthic Drugs

• Prevent ATP generation (Tapeworms)
• Alters membrane permeability (Flatworms)
• Neuromuscular block (Intestinal roundworms)
• Inhibits nutrient absorption (Intestinal
  roundworms)
• Paralyzes worm (Intestinal roundworms)

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Measuring Antimicrobial Sensitivity

• E Test
• MIC Minimal inhibitory concentration

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Measuring Antimicrobial Sensitivity Disk
Diffusion
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Antibiotic Resistance
Figure 20.20
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Antimicrobial Resistance

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

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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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Antibiotic Selection for Resistant Bacteria
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What Factors Promote Antimicrobial Resistance?

• Exposure to sub-optimal levels of antimicrobial
• 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

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

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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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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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MRSA mer-sah

• Methicillin-Resistant Staphylococcus aureus
• Most frequent nosocomial (hospital-acquired)
  pathogen
• Usually resistant to several other antibiotics

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Vancomycin Resistant Enterococci
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Vancomycin Use USA
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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