Principles of antimicrobial therapy Flashcards

1
Q

Targets of drug action

A
Enzymes
Receptors
Ion channels
Transporters
targets in host cell to later function
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2
Q

Immunity

A

Body’s ability to recognise and remove non-self material

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3
Q

Action of anti-microbial drugs

A

Ability to recognise and destroy non-self cells

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4
Q

What is chemotherapy based on?

A

Selective toxicity

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5
Q

What is selective toxicity?

A

Causes greater harm to micro-organism than host
Anti-microbial drugs must have limited toxicity but good selectivity
To increase efficacy= increase dose but efficacy and toxicity must be balanced

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6
Q

Chemotherapeutic index formula

A

Toxic Dose (lowest)/Therapeutic dose

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7
Q

Chemotherapeutic index meaning

A

The ratio of the minimal effective dose of a chemotherapeutic agent to the maximal tolerated dose

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8
Q

4 types of anti-microbial drugs

A

Anti-bacterial
Anti-fungal
Anti-protozoan
Anti-helminthic

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9
Q

Class I pathways that antimicrobial drugs target

A

Reactions that use glucose/other carbon sources to make ATP/substrates needed for class II reactions

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10
Q

Class II pathways

A

Pathways that use ATP and class I substrates to make small molecules e.g amino acids, nucleotides

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11
Q

Class III pathways

A

Convert small class II molecules into macromolecules e.g proteins, nucleic acids, polysaccharides, peptidoglycan

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12
Q

Name of a class II antimicrobial drug

A

Sulfonamide

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13
Q

What the pro drug of sulfonamide that is metabolized in the body to produce sulfonamide?

A

Prontosil

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14
Q

Sulfonamide mechanism of action

A

Competitive inhibitor of dihydropteroate synthetase
This enzyme normally produces folic acid
Prevent bacterial DNA synthesis and replication

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15
Q

Why can bacteria synthesise folate but humans can’t?

A

Bacteria have the enzyme dihydropteroate synthetase enzyme but humans don’t

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16
Q

What does dihydrofolate reductase catalyse?

A

Formation of tetrahydrofolate from dihydrofolate

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17
Q

What antimicrobial drugs prevent action of dihydrofolate reductase?

A

Trimethoprim
Methotrexate
Pyrimethamine

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18
Q

Mechanism of action of trimethoprim, methotrexate and pyrimethamine

A

(for trimethoprim) Type= antifolate antibacterial agent
Interaction- dihydrofolate reductase
Reversible inhibitor of dihydrofolate reductase
Tetrahydrofolate cant be made which is essential in making thymidine, nucleic acids and proteins (methionine)
so inhibits bacterial DNA synthesis
Killing bacteria

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19
Q

Example of a class III antimicrobial drug

A

Penicillin

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20
Q

What class of drug is penicillin?

A

Beta-lactam

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21
Q

Is penicillin broad/narrow spectrum antibiotic?

A

Narrow spectrum

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22
Q

Examples of Beta-Lactam drugs

A

Penicillins
Monobactams
Carbapenems
Cephalosporins

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23
Q

Bacteria cell wall peptidoglycan synthesis

A

Penicillin binding protein in cell wall e.g transpeptidase enzyme normally catalyses cross linking of peptidoglycan chains by binding to D-ALA D-ALA by transpeptidation reaction

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24
Q

What does beta-lactam do?

A

Inhibits peptidoglycan cell wall synthesis

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25
Q

Beta lactam mechanism of action

A

Beta-lactam ring mimics D-ALA D-ALA
beta lactam forms a covalent bond with amino aciid serine of transpeptidase enzyme
This inhibits transpeptidase carrying out the transpeptidation reaction required for peptidoglycan synthesis
no cell wall= lysis of bacteria by autolytic enzymes e.g autolysins

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26
Q

Antibiotics that inhibit cell wall synthesis

A

Vancomycin
Bacitracin
Cycloserine

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27
Q

Class III Anti-bacterial drugs can prevent synthesis of what?

A

Ribosomes

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28
Q

Eukaryotic ribosomes

A

80s
Large subunit= 60s
Small subunit= 40s

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29
Q

Prokaryotic ribosomes

A

70s
Large subunit= 50s (23sRANA)
Small subunit= 30s (16sRNA)

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30
Q

Why are ribosomes a good target for anti-bacterial drugs?

A

Bacteria ribosomes are different to eukaryotic ribosomes

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31
Q

What drugs target 30s subunit of bacteria ribosomes?

A

Aminoglycosides

Tetracyclines

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32
Q

Mechanism of action of Aminoglycosides

A

Targets 16sRNA of 30S subunit
Irreversibly bind to specific 30S-subunit proteins and 16S rRNA
Induces misreading of mRNA
incorrect amino acids are inserted into the polypeptide leading to non-functional or toxic peptides
halts protein synthesis

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33
Q

Mechanism of action of Tetracyclines

A

Broad spectrum
Passively diffuses through porin channels in the bacterial membrane
Reversibly binds to the 30S ribosomal subunit
preventing the attachment of aminoacyl-tRNA to the ribosomal A site (mRNA-ribosome complex)- in initiation of translation
Inhibiting bacterial growth by inhibiting translation

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34
Q

Which anti-bacterial drugs target the 50S large subunit of bacterial ribosomes?

A

Macrolides

Fusidic acid

35
Q

Macrolides mechanism of action

A

Broad spectrum
Bind to 50s subunit- to 23 S rRNA of 50S
Preventing the translocation of the elongation factor G (EF-G) from the ribosome
Inhibits polypeptide translocation and assembly of 50s subunit.

36
Q

Problem with bacterial ribosome-targeting drugs?

A

We have the same ribosomes in our mitochondria as bacteria

37
Q

Name of anti-bacterial drugs that target DNA arrangement?

A

Quinolones

38
Q

Quinolone mechanism of action

A

Prevents and inhibits DNA gyrase and topoisomerase from supercoiling and unwinding DNA
Inhibiting DNA replication

39
Q

Example of a quinolone

A

Ciprofloxacin

40
Q

Anti-bacterial drugs that target DNA synthesis

A

Quinolones

Metronidazole

41
Q

Anti-bacterial drug that target RNA polymerase

A

Rifampicin (inhibits RNA polymerase)

42
Q

Anti-bacterial drug that targets bacteria cytoplasmic phospholipid membrane

A

Polymyxins

43
Q

Anti-bacterial drugs that target protein synthesis (50s inhibitors)

A

Erythromycin

Lincomycin

44
Q

Anti-bacterial drugs that target protein synthesis (30s inhibitors)

A

Aminoglycosides

Tetracycline

45
Q

What are broad-spectrum drugs?

A

Active against a wider number of bacterial types
Used to treat a wide variety of infectious diseases
Useful when bacteria agent is unknown but likely to fall within a set of a certain species

46
Q

What are narrow spectrum drugs?

A

Used for specific infection when causative organism is known

47
Q

Advantage of narrow spectrum over broad spectrum drugs

A

Narrow spectrum drugs won’t kill as many of the normal microorganisms in the body like broad spectrum drugs do
so narrow spectrum drugs are less likely to produce GI side effects and/or residual drug reisistant strains

48
Q

What type of bacteria do polymyxins target?

A

Gram negative bacteria

49
Q

Examples of polymyxins

A
Polymyxin B 
Polymyxin E (colistin)
50
Q

Mechanism of action of polymyxins (colistin)

A

Colistin binds to LPS and phospholipids in outer membrane of gram-negative bacteria
Competitively displaces Ca2+ and Mg2+ from phosphate group of lipids in OM
Disrupts outer membrane= lysis

51
Q

What type of bacteria does vancomycin target?

A

Gram positive bacteria

52
Q

What is streptomycin an example of?

A

Aminoglycoside

Inhibits protein synthesis (30s)

53
Q

What type of cell wall do mycobacterium have?

A

Arabinogalactan

54
Q

Anti-bacterial drug that targets gram negative bacteria and mycobacterium

A

Streptomycin

55
Q

Why are anti-bacterial drugs good?

A

Clear difference between eukaryotic and bacterial cells

so easier to target bacterial cells

56
Q

Problem with anti-fungal drugs?

A

Fungi are also eukaryotic cells so little differnece between our cells and fungal cells

57
Q

What can anti-fungal drugs target in fungi?

A

Cell membrane

Cell division

58
Q

What anti-fungal drug targets fungi cell membrane?

A

Flucanozole

59
Q

What do fungi have in their cell membrane instead of cholesterol?

A

Ergosterol

60
Q

Fluconazole mechanism of action

A

Type- antifungal
Interacts- fungal cytochrome P450 dependent enzyme
Selective inhibitor of fungal cytochrome P450 dependent enzyme
This enzyme normally converts lanosterol to ergosterol
Inhibiting ergosterol synthesis
Disruption structure and function fungal membrane

61
Q

What anti-fungal drug disrupts cell structure/division in fungi?

A

Flucytosine

62
Q

Flucytosine mechanism of action

A

Type- antimetabolite
Fluctyosine is converted into fluorouracil (5FU)
5FU is converted into 5-fluorodeoxyuridylic acid (5dUMP)
5dUMP inhibits thymidylate synthase from converting dUMP to dTMP
preventing DNA synthesis

63
Q

Anti-viral drugs

A

Target various stages in virus’ life cycle

64
Q

What part of virus’ life cycle do anti-viral drugs target?

A

Entry into host cells
Nucleic acid replication
Viral protein synthesis
Virus exiting host cell

65
Q

Virus life cycle

A
  1. Virus attaches to receptor on host’s surface
  2. Virus attaches and enters host cell
  3. Uncoating of virus
  4. Genome replication of virus
  5. Protein and RNA synthesis of virus
  6. Assembly and maturation
  7. Released from host cell by neuraminidase
66
Q

What do anti-viral ion channel blockers do?

A

Prevent uncoating of virus in host cell

67
Q

What do integrases do?

A

Allow viral genome to integrate into host cell

68
Q

Anti-viral drugs that inhibit attachment and entry of virus into host cell

A

Maraviroc

Enfuvirtide

69
Q

Anti-viral drugs that block ion channels

A

Amantadine

Rimantadine

70
Q

Anti-viral drugs that inhibit DNA/RNA polymerase from being made

A

Acyclovir

Zidovudine

71
Q

Anti-viral drug that inhibits integrase enzymes

A

Raltegravir

72
Q

Anti-viral drugs that inhibit proteases

A

Saquinavir

Ritonavir

73
Q

Antiviral drugs that inhibit neuraminidase

A

Zanamivir

Oseltamivir

74
Q

What does viral neuraminidase do?

A

Allows virus to be released from host cell

75
Q

Viral entry inhibitor

A

Chloroquine

76
Q

Ribavirin and Favipiravir

A

Inhibit viral RNA dependent RNA polymerase

77
Q

Hydroxychloroquine

A

Inhibit viral entry

78
Q

Proteolysis

A

Spread viral proteins

79
Q

Inhibitors of proteolysis

A

Lopinavir

Ritonavir

80
Q

Ideal drug target

A

System in the infectious microorganism that doesn’t exist or exists in a different form in the host cell

81
Q

Class I biochemical processes

A

Common in most organisms so not a good target

82
Q

Class II and III

A

More likely to differ between organisms so a good target

83
Q

What are the mechanisms responsible for resistance of bacteria to anti-microbial drugs?

A
  1. Inactivating enzymes- beta lactamases break down beta lactam antibiotics (e.g monobactams)
  2. Decreased drug accumulation by:
    - Changing surface proteins e.g porins- bulk transporters- allow material to enter cells. Reduce no. of proins= reduce drug uptake into bacteria
    - Efflux pump- ejects drug out of cell (U-turn)
  3. Altering binding site- drug cant bind to it
  4. Development of alternative metabolic pathways - e.g sulfonamides and trimethoprim
84
Q

How do bacteria spread resistance?

A
  1. Spontaneous mutation- occurs as cells replicate
    some bacteria acquired resistance
    drug eliminates sensitive organisms
    resistant ones proliferate
  2. Gene transfer/ Transferred resistance- transfer of plasmid (extrachromosomal DNA)
    3.Pilli of bacteria can also help spread resistance