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MVST1B MODA > chemotherapy L3 > Flashcards

chemotherapy L3 Flashcards

1
Q

Antibiotics that act on DNA replication, and gene expression:

what are the 3 main targets?

A
  • A. Inhibitors of type II DNA topoisomerases
  • B. Inhibitors of RNA synthesis
  • C. Compounds that interact with dsDNA
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2
Q

DNA gyrase (type __ topoisomerase)

how does it work?

A
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3
Q

Topoisomerase IV operates by similar mechanism to DNA Gyrase; and remove ________

A

Topoisomerase IV operates by similar mechanism; remove concatemers​

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4
Q

2 main classed of drugs which inhibit DNA Gyrase?

A
  1. Aminocoumarins
  2. fluoroquinolones
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5
Q

fluoroquinolones are flurorated at position?

A

C6

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6
Q

charactersitics of aminocoumarins?

A
  • low water solubility
  • low activity against Gram- bacteria
  • target GyrB (ATPase domain)
  • drug resistance around 1980s
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7
Q

examples of fluoroquinolones?

A
  • Ciprofloxacin
  • levofloxacin
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8
Q
A
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9
Q

what are the fluoroquinolones widely used against?

A

widely used because of its activity against both gram-negative and gram-positive bacteria in urinary tract infections, osteomyelitis, community-acquired pneumonia, and gastroenteritis.

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10
Q

The newest generation of quinolones, such as gatifloxacin, have increased potency against….

A

The newest generation of quinolones, such as gatifloxacin, have increased potency against gram-positive pathogens.

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11
Q

inhibitors of the mammalian type II topoisomerases include ______ and _______, which are used in anticancer chemotherapy to kill rapidly growing tumour cells.

A

inhibitors of the mammalian type II topoisomerases include camptothecin and etoposide, which are used in anticancer chemotherapy to kill rapidly growing tumour cells.

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12
Q

do quinolones have a second target too?

A

yes

DNA topoisomerase IV (topo IV)

Like DNA gyrase, topo IV is a bacterial type II DNA topoisomerase, but unlike the DNA gyrase it cannot supercoil DNA. Instead, topo IV carries out the ATP-dependent relaxation of DNA and is a more potent decatenase than DNA gyrase.

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13
Q

how do quinolones affect Gyrase activity? (and type IV)

A

quinolones affect the double-strand cleavage/double-strand religation equilibrium in DNA gyrase and topo IV catalytic cycles, such that the cleaved complex accumulates.

unsure if it speed up cleavage or slows down reconnection.

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14
Q

fluoroquinolones

Synthetic antibiotics, broad spectrum, bactericidal. Inhibit ……… Relatively expensive.

A

Synthetic antibiotics, broad spectrum, bactericidal. Inhibit GyrA and GyrB. Relatively expensive.

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15
Q

Used in treatment of urinary tract infections.

what antibiotic?

A

fluoroquinolones

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16
Q

Ciprofloxacin is an FDA/MHRA approved drug against ….

A

Ciprofloxacin is an FDA/MHRA approved drug against

Bacillus anthrax in anthrax infections.

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17
Q

Levofloxacin (3rd generation FQ) has improved activity against …

A

Levofloxacin (3rd generation FQ) has improved activity against Gram+ Streptococcus pneumoniae

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18
Q

is rifampicin bactericidal?

A

yes

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19
Q

how does rifampicin work?

A
  • binds in tight but non-covalent manner to allosteric site on b subunit of the DNA- dependent RNA polymerase at a ratio of one mole of drug per mole of enzyme.
  • directly blocks the elongating RNA chain at the di- or tri-nucleotide stage by binding in the DNA/RNA tunnel associated with the b subunit
  • does not block synthesis in progress
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20
Q

does rifampicin block the exit tunnel for DNA dependant RNA polymerase

A

yes

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21
Q

rifampicin is used in …… infections.

A

Used in Mycobacterium tuberculosis infections.

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22
Q

whats special about rifampicins effects in vitro and in vivo?

A

Although rifampin inhibits fungal RNA polymerase in vitro, no significant effect against fungi…

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23
Q

Many rigid planar polycyclic antibiotics (e.g., …………) and synthetic compounds (e.g. …………….) interact with DNA by a mechanism known as intercalation.

describe intercalation

A

insert between adjacent stacks of DNA base pairs.

base don the preliminary unwinding locally to produce spaces.

affects dimensions of the major and minor groove - affecst enzyme binding

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24
Q

describe Bleomycins

A

metal-chelating glycopeptide antibiotics

Their action is thought to be based on the interaction between O2 and the bound iron, which generates superoxide and hydroxyl radicals causing single- and double- stranded breaks in DNA molecules

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25
Q

bleomycins are especially toxic to which cells?

A

These compounds are especially toxic to Gram-positive bacteria and mammalian cells

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26
Q

give a drug which induces covalent binding in DNA

A

Mitomycin C: alkylating agent

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27
Q

describe how mitomycin C works?

A

induces cross-linking between guanines at trans-

positions:

Used topically during eye-surgery to prevent scarring (glaucoma)

Mitomycin C does not act on naked DNA; it needs to be reduced in the cell, and forms reactive species during the cross-linking reaction

prevents strand separation during DNA replication and transcription.

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28
Q

Co-trimoxazole is a combination drug of …

A

Co-trimoxazole is a combination drug of sulfamethoxazole and trimethoprim.

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29
Q

Sulfamethoxazole and trimethoprim each block a step in the …..

A

Sulfamethoxazole and trimethoprim each block a step in the biosynthesis of folic acid

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30
Q
A
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31
Q

Sulfamethoxazole blocks the enzyme ….

A

Sulfamethoxazole blocks the enzyme dihydropteroate synthase (DHPS

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32
Q

trimethoprim inhibits……

A

trimethoprim inhibits dihydrofolate reductase (DHFR)

33
Q

Sulfamethoxazole blocks the enzyme dihydropteroate synthase (DHPS), while trimethoprim inhibits dihydrofolate reductase (DHFR). Both are key enzymes in the synthesis of …..

A

Sulfamethoxazole blocks the enzyme dihydropteroate synthase (DHPS), while trimethoprim inhibits dihydrofolate reductase (DHFR). Both are key enzymes in the synthesis of tetrahydrofolate,

34
Q

tetrahydrofolate is a what?

A

a methyl carrier coenzyme required for the biosynthesis of dTMP, and hence, DNA

35
Q

folate sources:

bacteria vs eukaryotes?

A

Bacteria have to make the folate skeleton de novo, while eukaryotes can scavenge folate from dietary sources and transport it into cells.

36
Q

describe how synergism is used in co-trimoxazole.

A
37
Q

are membranes tagets of some antibiotics?

A

yes

38
Q

Some bacterial nonribosomal peptide antibiotics, including……. act on the cytoplasmic membrane.

A

Some bacterial nonribosomal peptide antibiotics, including valinomycin, gramicidin A, polymixin and daptomycin act on the cytoplasmic membrane.

39
Q

how does valinomycin effect its toxicity?

A

ionophoretic capacity8

40
Q

why are antibiotics that act on the membrane bad for humans?

A

they ruin the PMF in our mitochondrion

41
Q

The ionophores _____ and _______ lose a proton as they bind K+ or Na+, respectively, and function as K+-H+ or Na+-H+ antiporte

A

The ionophores nigericin and monensin lose a proton as they bind K+ or Na+, respectively, and function as K+-H+ or Na+-H+ antiporte

42
Q

how precisely does valinomycin work?

A

The dehydrated K+ ion is coordinated precisely and specifically (about 104 greater affinity than Na+) to carbonyl groups in the hydrophilic interior of valinomycin. Because valinomycin is electroneutral, it carries the single (+) charge of the bound K+ ion. As valinomycin diffuses across the membrane, it functions as a K+ uniporter.

43
Q

describe Gramicidin A

A

dimeric ion channel

hydrophobic linear polypeptide antibiotic consisting of 15 amino acids and a carboxyterminal ethanolamine

Upon dimerisation in the membrane, this molecule forms a transmembrane ion channel that permits passive diffusion of monovalent cations with diameters of up to 5 Å

44
Q

valinomycins cation specificity?

A

Valinomycin and gramicidin A do not only interact with K+. Valinomycin has the cation specificity

Rb+ > K+ >> Na+ > Li+,

45
Q

gramicidin A cation specificity?

A

gramicidin A has the specificity

H+ > Rb+ > K+ > Na+ > Li+.

46
Q

describe how Polymyxin works?

A
  • associates with lipid bilayer phosphate heads
  • forms micells (like) complexes
  • affect the permeability of the cytoplasmic membrane.

*

47
Q

why are most drugs which act on the membrane toxic? and issues associated with this

A

In each of these cases the toxic effect of the antibiotic comes from the dissipation of transmembrane ion gradients, which disturb ion homeostasis and the energy metabolism, and induce leakage of macromolecules from the bacteria affected. A problem often associated with these compounds is their lack of selectivity, as the presence of a phospholipid bilayer is not restricted to bacteria.

48
Q

are cell membranes also the target for antifungal agents?

A

Cell membranes are also a target for antifungal agents, such as the polyenes amphotericin B and nystatin.

49
Q

how are polyenes amphotericin B and nystatin sleective for fungal membrane?

A

These amphipatic compounds exploit differences in the sterol composition of the fungal plasma membrane (ergosterol) and mammalian plasma membrane (mainly cholesterol) to be selective

The bind preferentially to ergosterol, facilitating the formation of pores for ions and macromolecules.

50
Q

Nystatin and Amphotericin B form___ _______ in the membrane

A

Nystatin and Amphotericin B form ion channels in the membrane

51
Q

polyenes such as Nystatin and Amphotericin B are active against which fungi?

A

active against Cryptococcus, Candida and Aspergillus and others

52
Q

polyenes interact preferentially with…

A

Interact preferentially with ergosterol, a fungal sterol, rather than cholesterol

53
Q

Antifungal synthetic triazoles (such as fluconazole) and imidazoles (such as miconazole) inhibit enzymes involved in…..

A

Antifungal synthetic triazoles (such as fluconazole) and imidazoles (such as miconazole) inhibit enzymes involved in ergosterol biosynthesis.

54
Q

which antifungal drugs inhibit ergosterol biosynthesis.

A

Antifungal synthetic triazoles (such as fluconazole) and imidazoles (such as miconazole) inhibit enzymes involved in ergosterol biosynthesis. Depletion of ergosterol alters fluidity of the membrane, thereby affecting permeability and the activity of membrane-associated enzymes.

55
Q

Antiprotozoal drugs can be roughly divided into two groups acting on …. what?

A

Antiprotozoal drugs can be roughly divided into two groups acting on (i) cellular integrity and (ii) biosynthesis of essential cofactors and macromolecules.

56
Q

what does Melarsoprol do?

whats it used to treat?

A
57
Q

describe Suramin

A

First useful anti-trypanosomal drug without a toxic metal atom. Therapeutic index is much higher than that of arsenicals

important drug against human trypanosomiasis (african sleeping sickness)

moleuar action unknown

58
Q

drugs used to treat Leishmania

A
  • Sodium stibogluconate (pentavalent antimonial) causes reduction in ATP and GTP and inhibition of DNA topoisomerase I
  • Plasma membrane of some Leishmania sp. contains ergosterol. Amphotericin B interacts and affects membrane permeability
  • Miconazole inhibits ergosterol biosynthesis
59
Q

In spite of their toxicity, arsenic and antimony compounds still retain a place in the treatment of ….

A

In spite of their toxicity, arsenic and antimony compounds still retain a place in the treatment of protozoal infections

60
Q

Arsenicals, such as _____ ______ that is generated from prodrug melarsoprol are preferentially toxic for Trypanosoma species.

This is probably due to ……

A

Arsenicals, such as melarsen oxide that is generated from prodrug melarsoprol are preferentially toxic for Trypanosoma species. This is probably due to selective uptake in these organisms.

61
Q

Another trypanocidal drug is suramin, which inhibits ……

These inhibitory actions interfere with the reoxidation of NADH and inhibit ATP synthesis.

A

Another trypanocidal drug is suramin, which inhibits glycerol-3-phosphate oxidase and NAD+-dependent glycerol-3-phosphate dehydrogenase.

These inhibitory actions interfere with the reoxidation of NADH and inhibit ATP synthesis.

62
Q

how does chloroquine work as an antimalarial drug?

A
  • During erythrocytic cycle, Plasmodium uses hemoglobin as a nitrogen source.
  • Toxic heme would accumulate to toxic levels (200 - 500 mM!). This would cause the formation of reactive oxygen species.
  • Toxic heme is polymerised into non-toxic hemozoin in food vacuole.
  • Chloroquine inhibits the formation of hemozoin (either by inhibiting
  • polymerase or through complexation of heme).
  • Chloroquine raises pH in food vacuole, reduced metabolism
63
Q

give some other antimalarials in the chloroquine class?

A

Other drugs in this group are quinine, mefloquine, and primaquine

64
Q

chloroquine is used to treat

A

malaia

65
Q

artemisinin speed of acting?

A

rapid onset

66
Q

artemisinin exert its antimalarial activity through the generation of ….

A

artemisinin exert its antimalarial activity through the generation of highly reactive organic free radicals

67
Q

artemisinin

A
68
Q

(artemisin combination therapy.

artemisin is administerd with/…

A

primaquine

69
Q

do many parasites need, like bacteria, to synthesize their own folic acid?

A

yes

70
Q

T or F

Like many bacteria, several parasites cannot use preformed folates for nucleic acid synthesis and must synthesize them.

A

T

71
Q

how does sulfadoxin work?

whats it used to treat?

A

Like many bacteria, several parasites cannot use preformed folates for nucleic acid synthesis and must synthesize them.

The metabolic pathway used, is dependent on p-aminobenzoate (as we have seen for bacteria, p. 25), and are therefore susceptible to p-aminobenzoate analogues, such as sulfadoxin (a sulfa drug), that competitively inhibit the action of dihydropteroate synthase (DHPS).

72
Q

Further along in the folate pathway, the conversion of dihydrofolate into tetrahydrofolate by dihydrofolate reductase (DHFR) is susceptible to the trimethoprim analogue ________

A

Further along in the folate pathway, the conversion of dihydrofolate into tetrahydrofolate by dihydrofolate reductase (DHFR) is susceptible to the trimethoprim analogue pyrimethamine

73
Q

Pyrimethamine (analogue of trimethoprim) inhibits ______

A

Pyrimethamine (analogue of trimethoprim) inhibits DHFR

74
Q

Sulfadoxin and pyrimethamine are used in combination as ________ (analogous to co-trimoxazole) against ….

A

Sulfadoxin and pyrimethamine are used in combination as Fansidar (analogous to co-trimoxazole) against Plasmodium falciparum

75
Q

describe Proguanil

A

Proguanil is used as a prophylactic prodrug.

Is converted into cycloguanil, which inhibits plasmodial dihydrofolate reductase

76
Q

However, two classes of antibiotics, _______ and ___________, surprisingly show activity against certain protozoa, including Plasmodium.

A

However, two classes of antibiotics, tetracyclines and lincomycins, surprisingly show activity against certain protozoa, including Plasmodium.

77
Q
A
78
Q

fat

A

mamba

MVST1B MODA (22 decks)

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