Antimicrobial chemotherapy - agents and mechanisms of action Flashcards

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1
Q

When are antimicrobial agents therapeutically useful?

A

Useful if the target is;

  • not present in man
  • if microorganism has higher affinity for the drug than man
  • most antibiotics in clinical usage are directed against bacterial cell wall synthesis, bacterial ps or bac nucleic acid synthesis
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2
Q

Selective toxicity?

A
  • Must be highly effective against microbe but have minimal or no toxicity to humans
  • In practice it is expressed y a drug’s therapeutic index (TI) - ratio of the toxic dose to the pt to the therapeutic dos to eliminate the infec
  • larger the index = safer the drug is
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3
Q

What are antimicrobial agents? Types?

A

Can be narrow (either gram pos or neg) or broad spectrum (against gram pos and neg)
Control specific infecting organisms

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4
Q

Desirable characteristics of antibiotics?

A
  • Wide spectrum activity and can destroy or inhibit many different species of pathogenic organisms
  • Non-toxic to host
  • No undesirable side effects
  • Non-allergenic
  • Reach body part with infec
  • Not eliminate normal flora of host
  • Cheap, easy to produce
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5
Q

How are antimicrobials classified?

A

By chemical structure, target site and according t whether they are bactericidal (kill) or bacteriostatic (inhibit growth)

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6
Q

What are the main targets for antimicrobials?

A
  • Cell wall - peptidoglycan
  • PS - ribosomes or enzymes
  • Metabolic pathways
  • DNA
  • Membranes
  • Enzymes
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7
Q

How to test for antibiotics?

A

Disc diffusion on agar - if bac sensitive to antibiotic = clear zones formed

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8
Q

How to test for antibiotics in liquid?

A

MIC/MBC test
MIC = minimal inhibitory conc = min antibiotic needed to inhibit bac growth = conc that stops growth = clear broth
MBC - minimal bactericidal conc = min. to kill bac = lowest conc where no colonies formed = clear plate
Add same amount of bac to each tube and decrease conc of antibiotic in each tube

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9
Q

Cell wall targets?

A

Peptidoglycan = unique, needs to be crosslinked = AA crosslinked

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10
Q

What are the main classes of agents that act against the cell wall?

A
  • Beta-lactams - penicillins and cephalosporins
  • Glycopeptides - vancomycin
  • Cycloserine - inhibits alanine racemase
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11
Q

Beta-lactam antibiotics?

A

Bactericidal compounds, contain beta-lactam ring and inhibit normal cell wall formation
Beta-lactam ring can have diff structures attached;
- penicillins - 5 membered
- cephalosporins - six-membered

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12
Q

What do beta-lactam’s do?

A

Inhibit peptidoglycan formation

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13
Q

How does penicillin’s structure aid it’s function?

A

Mimics structure of D-ala-D-ala = inhibits formation of peptidoglycan cross-links in the bacterial cell wall by binding of the 4-membered beta-lactam ring of penicillin to the enzyme DD-transpeptidase
DD-transpeptidase cannot then catalyse formation of these crosslinks = cell death

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14
Q

Vancomycin?

A

Effective against Gram positive organisms
Binds to D-alanyl D-alanine dipeptide on side chain of newly synthesised peptidoglycan subunits, preventing them from being incorporated into cell wall by penicillin binding proteins (PBPs)

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15
Q

How do antibiotics inhibit protein synthesis?

A
  • Aminoglycosides – bind to 30S subunit & cause misreading of genetic code
  • Tetracyclines – inhibit binding of tRNA to mRNA – ribosome complex
  • Erythromycin – binds to a molecule in 50S subunit blocking exit of nascent polypeptide chain
  • Fusidic acid – ‘elongation factor G (EFG)’ – bacterial protein needed for translocation on bacterial ribosome after peptide bond formation during protein synthesis. Fucidic acid binds EFG preventing protein synthesis.
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16
Q

Aminoglycosides?

A

Bind to 30S subunit = misreading of genetic code
contain an aminocyclitol ring linked to a sugar
Effective against aerobes and facultative anaerobes
Not active against anaerobes

17
Q

Why are aminogylcosides not effective against anaerobes?

A

Bacterial up-take requires oxygen- or nitrate-dependent electron transport

18
Q

Problem with aminoglycosides?

A

Not absorbed from the gut
must be given intravenously or intramuscularly for systemic treatment
Side effects – nephrotoxicity, ototoxicity

19
Q

Tetraclyclines?

A

Inhibit binding of tRNA to mRNA/ribosome complex

  • Bacteriostatic compounds = all broad spectrum, penetrate mammalian cells = reach intracellular organisms, incorporated in developing bone and teeth
  • Use restricted due to resitance
20
Q

Macrolides?

A
  • Bind to 50S subunit blocking exit of nascent polypetide chain
  • Large cyclic molecules containing macrocyclic lactone ring - bacteriostatic
  • Erythromycin most commonly used = e.g. for penicillin allergic pts - penetrates mammalian cells to reach intracellular organisms
21
Q

What are the agents that affect DNA? How?

A
  • Quinolones - Target site is DNA gyrase – DNA gyrase is a topoisomerase that relieves strain while DS DNA is being unwound by helicase.
  • Rifamycins – inhibit DNA dependent RNA synthesis due to high affinity for bacterial RNA polymerase (poor affinity for mammalian)
  • Metronidazole - disrupts DNA – only works when it is reduced and as this reaction only usually happens in anaerobic cells – effective against anaerobes
22
Q

Nitroimidazoles?

A

Disrupt DNA

E.g metronidazole, tinadazole = antiparasitic and antibac properties

23
Q

How does metronidazole work?

A
  • Activated in cell by redox enzyme pyruvate-ferredoxin oxidoreductase
  • In anaerobes, ferredoxin is an e- transporter molecule that reduces (gives electrons to) Metronidazole
  • This single electron transfer reduces nitro group of met. creating highly reactive anion – disrupts DNA helix
    intermediate is short-lived and decomposes
  • Metronidazole is active only against strictly anaerobic organisms
    because only these can produce the low redox potential necessary to reduce the drug.
24
Q

Which antibiotics interfere with metabolic pathways?

A
  • Folic acid enzymes = needed for AA synthesis and PS
  • E.g Sulfonamides = inhibit these enzymes
  • Active against gram pos and neg
25
Q

Problem with metabolic pathway antibiotics?

A

Resistance

26
Q

Define antibiotic resistance

A

Organism that is not inhibited or killed by an antibacterial agent at concentrations of the drug achievable in the body after normal dosage.

27
Q

How is antibiotic resistance developed?

A

Chromosomal mutation
Coded for by plasmid DNA
Plasmids are transmissible
Transposons can carry resistance genes and jump between chromosome and plasmid

28
Q

How is antibiotic resistance transferred?

A

Cassettes of multiple resistance genes can be organised into genetic elements called integrons
Integrons contain gene for recomination enzyme to allow insertion

29
Q

Mechanisms of antibiotic resistance?

A
  • The target is structurally altered (by mutation)
    Now has a lower affinity for the antibacterial
    Pencillin-binding proteins
- The target is overproduced
Dihydropteroate synthetase (bacterial target) and sulphonamide
  • The drug is not activated
    Aerobes and metronidazole
  • The drug is removed
    Enzymic destruction
    β-lactamase
    3 modifying enzymes responsible for acquired aminoglycoside resistance
  • Efflux
    Tetracyclines, quinolones
  • The drug cannot gain entry to the cell
    outer-membrane barrier, lack of transport mechanism
30
Q

Antivirals?

A

Few in number
Narrow spectrum
Virustatic
Need to interfere with viral machinery without effecting host

31
Q

How do antivirals work?

A

1)Penetration/uncoating
Amantadine
Prevent fusion of viral envelope with cell membrane
2) Taking over cell machinery
- Transcription
Nucleoside analogues - Zidovudin, acyclovir
Zidovudin (AZT) acts as substrate for & inhibitors of viral reverse transcriptase
Acyclovir – inhibits HSV DNA polymerase
- Translation
anti-sense morpholinos (oligomer molecules that block target sequence in RNA by binding); ribozymes (cut viral RNA)

32
Q

Post-translation inhibition of antivirals?

A

Post-translation inhibition;

  • Protease inhibitors
  • Protease cleaves viral polyproteins into structural proteins required for viral replication
  • Protease inhibition – immature, defective viral particles - HAART (highly active antiretroviral therapy)