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Unit 3 > W1: Antimicrobial chemotherapy > Flashcards

W1: Antimicrobial chemotherapy Flashcards

1
Q

What is the relationship between antimicrobials and the bodies own immune system?

A

Antimicrobials are given when the body’s own immune system is struggling to fight a microbe-caused disease.
Antimicrobials will kill MOST of the microbes or stop them from replicating.
The body’s own immune system then finishes the job.

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2
Q

What is meant by microbial flora?

A

The community of microorganisms that live on or in a particular organism/ object in a certain environment.

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3
Q

What is meant by selective toxicity in relation to drugs?

A

Drugs are desgined to only kill a specific type of cell e.g bacteria.
This means drugs target mechanisms or properties of abnormal or non-self cells which are not needed for healthy self cells survival, so causes greater harm to the microorganism compared to the host.
Is a balance between a working dose and a dose that is toxic to healthy cells.

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4
Q

What is meant by chemotherapeutic index?

A

A measure of the difference between a therapeutic and a toxic dose.
The larger the number the larger the gap.
Calculated by dividing the toxic dose by the therapeutic dose.

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5
Q

What is meant by a chemotherapeutic agent?

A

A drug that uses selective toxicity to kill abnormal or non-self cells. Works alongside the immune system by killing or preventing the replication of cells.

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6
Q

What is an antimicrobial drug?

A

A type of chemotherapeutic that kills microbes.
Includes antibacterial, antifungal etc

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7
Q

What is meant by the term ‘class’ when referring to antimicrobials?

A

A grouping or classification of antimicrobials based on what their target is.

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8
Q

What classification of drug is a sulfonamide?
Explain its mechanism of action.

A

A class two synthetic antibacterial drug.
Targets dihydropteroate synthase, this is an enzyme used in early synthesis of bacterial folic acid but is not involved in the pathway in humans.
Inhibts this enzyme, hence inhibits purine, amino acid and thymidine synthesis (DNA, RNA and proteins inhibited).
Stops bacteria replicating.

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9
Q

What is the clinical application of a sulfonamide?

A

Sulfonamide is broad spectrum bacteriastatic drug.
Used for most gram positive and some gram negative bacteria.
May be combined with other drugs such as trimethoprim to be cidal.

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10
Q

Explain the basic mechanism behind trimethoprim, methotrexate and pyrimethamine.

A

Inhibits the dihydrofolate enzyme found in bacteria (different tertiary structure than that of humans).
Inhibits folic acid metabolism.
Prevents the synthesis of protein, DNA and RNA.

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11
Q

What is noticeable of the IC50 of trimethoprim?

A

Bacteria IC50 is significantly lower than others (humans and protest).
So has a large chemotherapeutic index, so is very safe for use in humans to kill bacteria.

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12
Q

What is noticeable of the IC50 of pyrimethane?

A

Significantly lower for protists/fungi than bacteria and humans.
Is used to treat fungi and protists, not bacteria as bacterial IC50 is closer to humans.

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13
Q

What is noticeable about the IC50 of methotrexate?

A

Is very similar for bacterial 0.1, fungal 0.7 and mammalian 0.2.
The explains the adverse effects of chemotherapy in cancer patients.

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14
Q

What is meant by a structural analogue?

A

Similar in structure to another compound.

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15
Q

What is the action of trimethoprim?

A

Is a structural analogue of DHF in folic acid metabolism.
Inhibts dihydrofolate reducatase as a competitive inhibitor of DHF, forms hydrogen bonds with enzyme.
This prevents the reduction of DHF to THF.
This prevents the synthesis of purines and thymidylate.
Disruption is DNA synthesis leads to cidal activity.

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16
Q

What is the clinical application of trimethoprim?

A

Used in isolation or in combination with sulfamethoxazole to treat infections of the urinary, respiratory and gastrointestinal tract.
Also for parasitic malaria and cancer as antiproliferative effects.

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17
Q

What are some typical targets for antibacterial drugs?

A

Cell wall integrity
Cell wall synthesis
DNA synthesis
DNA gyrase
RNA polymerase
Phospholipid membrane
Translation 50s and 30s unit of the ribosome.

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18
Q

What are the layers of a myobacterial cell wall from outside in?

A

Extractable phospholipids, myocolic acids and arabinoglactan (spanned by pores).
Peptoglycan
Cytoplasmic membrane.

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19
Q

What drugs might be used to interfere with bacterial cell wall synthesis?

A

B-lactams - inhibits transpeptidases to prevent cell wall synthesis.
Cycloserine - prevents synthesis of NAM subunits
Baciteracin - prevents synthesis of peptidoglycan polymers
Vancomycin - prevents crosslinking of peptidoglycan chains.

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20
Q

What is a penicillin-binding protein?

A

A protein, often in the cell wall of a bacteria that can be bound to by penicillin.

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21
Q

What is a transpeptidase enzyme?

A

A penicillin binding protein.
Is an enzyme that when functional catalyses the cross-linking of peptidoglycan polymers in bacterial cell wall synthesis.

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22
Q

What are b-lactams?
Some examples.

A

Category of drugs that interfere with bacterial cell wall synthesis by inhibiting the transpeptidase enzyme preventing cross linking.
Have cidal action
Includes penicillins and cephalosporins.

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23
Q

What is important about the structure of b-lactams?

A

Mimic the structure a D-ala-D-ala so are able to form hydrogen bonds with, hence occupy the transpeptidase active site as a competitive inhibitor.
Contains a blactam ring:

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24
Q

What is the chemistry and clinical application of amoxicillin?

A

Is a beta lactam drug.
Used for bacterial infections nose, ear, GI tract etc.
May be combined with omeprazole to treat helicobacter pylori infections

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25
Q

What type of bacteria are beta lactams mainly used for?

A

Gram-positive
(may be used for other types- but is generally narrow spectrum)

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26
Q

Describe and contrast the structure of prokaryotic and eukaryotic ribosomes.

A

Prokaryotic - 50s and 30s give a 70s ribosome
Eukaryotic - 60s and a 40s give an 80s ribosome

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27
Q

What is the mechanism of action for amoxicillin?

A

Competitive inhibitor of D-ala-D-ala so occupies transpeptidase enzymes, prevent cell wall synthesis and causes upregulation of autolytic enzymes.
Has a cidal effect.

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28
Q

What is gentamicin?

A

An aminoglycoside.
Induces misreading to halt protein synthesis, must be used in high concentrations.
Targets the 30s unit of prokaryotic ribosomes,

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29
Q

What is clarithromycin?

A

A Macrolide.
Inhibits translocation.
Targets the 50s unit of prokaryotic ribosomes.

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30
Q

Explain the clinical and chemical properties of clarithromycin?

A

Consists of a large ringed structure (15 atoms) with smaller joining rings.
Used to treat respiratory tract infections and skin/soft tissue infections with bacteria.
May also be used to treat lyme disease, helicobater pylori and parasitic infections.

31
Q

What is the mechanism of action of clarithromycin?

A

Binds reversibly to the 50s ribosomal subunit in prokaryotes.
Inhibits translocation of the aminoacyl tRNA hence peptide chain elongation.
Causes cell death as cell unable to produce new proteins.

32
Q

What is the function of DNA gyrase?

A

Unfolds bacterial chromosomes within the nucleoid so they can be read and genes expressed.

33
Q

What is the chemical structure of quinolones?

A

Have a bicyclic ring.
Flouro- indicates a flourine is attached to the ring.

34
Q

What is the function of quinolones?

A

Antimicrobial drug, target DNA gyrase.

35
Q

What is the mechanism of action for ciprofloxacin?

A

Is a flouroquinolone.
Targets DNA gyrase to prevent the uncoiling of chromosomes in prokaryotes.
Promotes double stranded DNA cleavage and cell death.
Binding is reversible.

36
Q

What are some clinical applications of ciprofloxacin?

A

Provide NB resistance and fight pseudomonas spp.
Used for many bacterial infections.

37
Q

What is meant by drugs having different spectra of activity and why is each spectra useful?

A

Spectra refers to the range of different microbes that a drug can treat.
Broad spectrum - as used when the specific causative microbe is not known but it is likely to be of a certain set of species
Narrow spectrum - are used to target the microbe when the species in known, less likely to promote the growth of antibiotic resistance and have less gastrointestinal side effects.

38
Q

What are polymixins?

A

A narrow spectrum class of drug, used as a last resort on gram negative bacteria.
Has detergent like action to dissolve the phospholipid membrane.
Neutralises lipopolysaccharides on bacterial surface so less likely to enter host

39
Q

Give an example of a broad spectrum antibiotic.

A

Tetracyclines

40
Q

What type of antibacterial drug will target cell wall integrity?

A

Beta lactamases (check padlet)

41
Q

What type of antibacterial drug will target DNA synthesis?

A

Metronidazole

42
Q

What type of antibacterial drug will target DNA Gyrase?

A

Quinolones

43
Q

What type of antibacterial drug will target RNA polymerase?

A

Riframipicin

44
Q

What type of antibacterial drug will target the phospholipids in the cell membrane?

A

Polymyxin

45
Q

What type of antibacterial drug will target translation?
50s
30s

A

Macrolides (clarithromycin) and fusidic acid
Aminoglycosides (gentamicin) and tetracyclin.

46
Q

Explain the action of fluconazole?

A

Targets the endoplasmic reticulum, and prevents ergosterol synthesis, this inhibits the synthesis of fungal cell walls.
Cidal activity

47
Q

What are the different targets for antifungal drugs?

A

Mitotic spindles
DNA synthesis
Plasma membrane
Cell wall

48
Q

What type of antifungal drug targets the mitotic spindles?

A

Griseofulvin

49
Q

What type of antifungal drug targets the DNA synthesis?

A

Flucytosine

50
Q

What type of antifungal drug targets the plasma membrane?
What makes this drug more difficult to use?

A

Polyenes (note insoluble) such as amphotericin B.
Has a low chemotherapeutic index

51
Q

What type of antifungal drug targets the cell wall?

A

Echinocandins

52
Q

How do antifungal prodrugs work?

A

Pro-drugs are converted to active metabolites within fungal cells,
Pro-drugs are not converted to active metabolites, so remain inactive in host organisms.

53
Q

Explain the mechanism of action of flucytosine.

A

Flucytosine is taken up by fungal cells through the cytosine permease transported.
Is a pro-drug so is converted to the active form 5-FdUMP, this is inserted into DNA and prevents further elongation.

54
Q

What are the different antiviral drug workings?

A

Attachment and entry inhibitors
Ion channel blockers
Polymerase inhibitors
Integrase Inhbitors
Protease Inhibitors
Neuroaminidase inhibitors.

55
Q

Give examples of antiviral drugs that target attachment and entry,

A

Maraviroc
Enfuvirtide (T-20)

56
Q

Give examples of antiviral drugs that target viral protein synthesis by inhibiting proteases?

A

Saquinovir
Ritonavir

57
Q

Give examples of antiviral drugs that target neurominidase catalysed cleavage to prevent exit from host cells.

A

Oseltamivir
Zanamivir

58
Q

Give examples of antiviral drugs that target viral protein synthesis by polymerase inhibition.

A

Acyclovir
Zidovudine

59
Q

Give some examples of virl intergrase inhibitors

A

Raltegravir

60
Q

Give some examples of ion channel blockers as antiviral drugs.
What is the basic idea od how they work?

A

Amantadine
Rimantadine
Block ion channels, prevents viral uncoating as virus unable to release genetic material into the host cell.

61
Q

How is camostat mesylate and arbidol used to treat covid?

A

Prevent entry into host cells,
Inhibit the biding of viral s protein to receptors on the cell surface membrane of the host cell.

62
Q

How is chloroquine used in the treatment of covid?

A

Prevents entry into host cells by inhibiting fusion and endocytosis.

63
Q

How is lopinavir-ritonavir used to treat covid?

A

Previously used to treat HIV.
Inhhibits protease enzyme, so large polypeptides and not broken down into amino acids (inhibited proteolysis).
So new proteins can not be formed.

64
Q

How is ribavin used to treat covid?

A

Prevents viral RNA dependent RNA polymerase, y inhibiting enzyme, so inhibits transcription.

65
Q

How is tocilizumab used to creat covid 19?

A

Is a monoclonal antibody, acts as a structural analogue to interleukin 6, hence binds to interleukin 6 R as a competitive inhibitor.
This reduces the post infection immune response, for example has anti-inflammatory properties.

66
Q

What are the three stages in drug testing?

A

Pre-clinical (testing on tissue and computer predicted models)
Animal - identity toxicity
Clinical in healthy the ill humans - dosage

67
Q

How does the use of antivirals and antifungals compare to antibacterial?

A

V and Fs are prescribed less frequently, drugs are perceived as less effective.
Aim to give a more localised dose rather than systemic, so are often topical.

68
Q

What class of drug is easier to develop for antimicrobials?

A

Class 2 and class 3.
More comples processes are more likely to have differences between organisms than simpler processes (such as class 1 drug targets)

69
Q

How has resistance to penicillin changed over time?

A

Originally only 3% of targets were resistant to penicillin, now 90% of targets are resistant to penicillin.

70
Q

What are the two methods by which resistance may arise?

A

Spontaneous mutation
Gene transfer

71
Q

What are the four possible mechanisms by which antimicrobial resistance can occur?

A
  1. Activating enzymes that destroy the drug (called inactivating enzymes)
  2. Decreasing drug accumulation either by increased elimination or decreased uptake
  3. Altering the drug binding sites
  4. Development of alternative metabolic pathways.
72
Q

What are beta lactamases?

A

Enzymes found in bacteria that hydrolyse the beta lactam ring in drugs to create inactive metabolites, hence give resistance to beta lactam drugs such as penicillin.

73
Q

What is co-amoxiclav?
How does is work?

A

Co-amoxiclav is a combined antibacterial therapy.
Made of clavulanic acid - acts as a distraction, is targeted by hence occupies beta lactamases, is not a problem that it is destroyed as it has low antimicrobial activity anyway.
Amoxicillin - is a beta lactam, prevents cell wall synthesis by targeting transverse peptidase enzyme

74
Q

How can we slow the emergence of antibiotic resistance?

A

Understand the mechanism behind antibiotic resistance.
Use combination therapies
Ensure physician identifies the microbe, gives the appropriate antibiotic and does not over prescribe.
Patient must follow the instructions for their antibiotics and finish the course of treatment.

Unit 3 (18 decks)

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