Antimicrobial Drugs and Drug Resistance

Question 1

What is Antimicrobial Drugs?

Answer 1

• Used when immunization has not occurred and the immune system has
  difficulty to eliminate infection
  
  • Useful against bacterial infection, very few antivirals are available
• These are compounds that kill or control the growth of microorganisms in
  the host
  
  • These drugs must display selective toxicity or they will cause damage to the host

Question 2

What is the two broad categories of Antimicrobial Drugs?

Answer 2

1. Synthetic and natural
   
   • Large number of naturally occurring antibiotics with no clinical use
     
     • Produced by bacteria and fungi
2. Can be described based on whether they are:
   
   • Bacteriostatic or bacteriocidal
   • Broad spectrum or narrow spectrum

Question 3

Cell Wall Active Antimicrobial Drugs

Answer 3

• Cell wall active agents offer excellent selective toxicity
  
  • Most widely used class of antibiotics

Question 4

Beta Lactam Antibiotics

Answer 4

• Largest Class
• Common feature is the b-lactam ring
• Naturally occurring: produced by Penicillium and Cephalosporium fungi
• Example: penicillins and cephalosporins
• Can be modified in the lab to produce semi-synthetic drugs that have a modified spectrum of activity
• Susceptible to beta-lactamases
  
  • Enzyme produced by some bugs to cut and inactivate beta-lactams

Question 5

Penicillins

Answer 5

• Narrow spectrum of activity
  
  • Characterized by a five membered ring attached to the beta-lactam component
  • Target transpeptidation in gram positive bacteria
  • Cannot penetrate outer membrane of gram negative bacteria
    
    • Semi-synthetic penicillin are modified to provide some activity against gram negative bugs
      
      • Example: ampicillin

Question 6

Cephalosporins

Answer 6

• Structurally distinct from penicillins
  
  • Six membered ring is attached to the beta-lactam component
• Also target transpeptidation of peptidoglycan
• Many semi-synthetic examples
• Broader spectrum of activity than penicillin
• Better resistance against beta lactamases
• Grouped into generations
  
  • 1st generation cephalosporin, 2nd generation cephalosporin etc.

Question 7

Growth Factor Analogs

Answer 7

• Growth factor analogs are structurally similar to growth factors but do not function in the cell
  
  • Analogs similar to vitamins, amino acids, and other compounds

Question 8

Growth Factor Analogs (Example: Sulfa Drugs)

Answer 8

• Example: sulfanilamide
• Inhibit growth of bacteria by inhibiting folic acid synthesis and thus nucleic
  acid synthesis (We can’t synthesis on out own)
• Often used in combination with another analog→ trimethoprim
  
  • Combination therapy minimizes the likelihood of resistance

Question 9

Growth Factor Analogs (Example: Isoniazid)

Answer 9

• Extremely narrow spectrum cell wall active agent
• Analog of mycolic acid component needed by Mycobacterium spp.

Question 10

Nucleic Acid Synthesis Inhibitors (Quinolones)

Answer 10

• Synthetic antimicrobials
• Inhibit DNA gyrase
  
  • Prevents supercoiling of DNA
• Active against both Gram-negative and Gram-positive bacteria
• Example: ciprofloxacin a fluorinated quinolone (fluoroquinolone)
  
  • Useful against life threatening infections
• Rifampin: binds to RNA polymerase preventing transcription
• Actinomycin: Binds to DNA template blocking transcription elongation

Question 11

Protein Synthesis Inhibitors

Answer 11

• Protein synthesis inhibitors target 70S ribosomes
  
  • Good selective toxicity
  • Some issues because human cells have 70S ribosomes in the mitochondrial matrix

Question 12

What are included in Protein Synthesis Inhibitors?

Answer 12

1. Aminoglycosides
2. Tetracycline
3. Macrolides

Question 13

Aminoglycosides

Answer 13

• Bind to the 30S subunit of 70S ribosomes
• Block translation
• Narrow spectrum
  
  • Useful against gram negative bugs
• Often used as a last resort drug
• Damaging to the kidneys and ears
• Examples include streptomycin, gentamycin and neomycin

Question 14

Tetracycline

Answer 14

• Broad spectrum
• Produced by species of the Streptomyces genus
• Bind to the 30S subunit
• Consist of both natural and modified semisynthetic
  drugs
• Binds to calcium damaging teeth and bone
  
  • Shouldn’t be used in children and pregnant
    women
• Used in veterinary medicine and to promote animal growth
  
  • Creates problems with resistance

Question 15

Macrolides

Answer 15

• Broad spectrum of activity
• Bind to the 50S ribosomal subunit
  
  • Only inhibits translation of some proteins
  • Some proteins are preferential translated and others are not
    
    • Creates a detrimental protein imbalance inside of the cell
• Useful to treat infection in patients with allergies to beta lactam antibiotics
• Example: erythromycin and azithromycin
  
  • Produced by Streptomyces spp.

Question 16

Novel Antibiotics

Answer 16

• Daptomycin
  
  • Produced by Streptomyces spp.
• Cyclic lipopeptide
  
  • Active against Gram-positives
    
    • Pathogenic Staphylococcal spp. and
      Streptococcal spp.
• Forms pores in the plasma membrane causing depolarization
  
  • Cell cannot synthesize necessary biomolecules
    
    • Cell death occurs
• Resistance can occur when bacteria alter plasma
  membrane composition

Question 17

Antibiotic Resistance

Answer 17

• Antibiotic resistance occurs when an organism develops a mechanism to elude the activity of an antimicrobial drug that it should otherwise be susceptible to
  
  • Genes for antibiotic resistance can either be encoded on a plasmid or directly within the genome
• Resistance is prevalent because of widespread and sometimes incorrect use of antibiotics
  
  • Medicine, veterinary medicine, agriculture

Question 18

What are the mechanisms and examples?

Answer 18

• Reduced permeability -> Penicillins
• Inactivation of antibiotic -> Penicillins, Chloramphenicol, Aminoglycosides
• Alternation of target -> Erythromycin, Streptomycin, Norfloxacin
• Development of resistant biochemical pathway -> Sulfonamides
• Efflux -> Tetracyclines, Chloramphenicol, Fluoroquinolones

Question 19

Patterns of Antibiotic Resistance

Answer 19

• Emergence of antibiotic resistance in different species of bacteria
• Patterns of antimicrobial resistance

Question 20

Preventing Antibiotic Resistance

Answer 20

• Infection prevention -> Void getting sick
• Rapid and conclusive diagnosis -> Right for treatment but bad for antibiotic resistance
• Appropriate/prudent use of antibiotics -> Use it when you only need it NO OVERUSE (Prescription)
• Prevention of transmission - Stay home and be careful