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KOKN01 - Medicinal chemistry > Dugga 3 - Antibacterial > Flashcards

Dugga 3 - Antibacterial Flashcards

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1
Q

Is vancomycin used on gram negative bacteria?

A

No, because vancomycin is such a large molecule it is unable to pass the outer cell membrane.

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2
Q

What are the 5 main strategies that antibacterial drugs is developed from?

A
  1. Antimetabolites = inhibition of the cell metabilism. Ex inhibit an enzyme-catalyzed reaction present in a bacterial cell
  2. Inhibition of bacterial cell wall synthesis
  3. Interactions with the plasma membrane
  4. Disruption of protein synthesis
  5. Inhibition of nucleic acid transcription and replication
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3
Q

Vancomycin uses dimerization and through that sterically hindering the two enzymes to interact with the L-lys-d-Ala-d-Ala tail of the cell wall building block, which ones?

A

Transglycosidase - catalyzes the attachment of the disaccharide building block to the growing cell wall.

Transpeptidase enzymes - the enzyme is responsible for the crosslinking between the various chains of the cell wall

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4
Q

What is two factors important for vancomycins rigdification and specification?

A

Fixed conformation of hexapeptide chain.

The aromatic rings are prevented from becoming coplanar

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5
Q

Mention some analogues to vancomycin

A
  • Teicoplanin
    -Dalbavancin
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6
Q

Glycopeptides are slow in causing resistance in bacteria, why?

A

Attack bacteria in three different ways:

  1. Block enzymes by acting as a steric sheild for the tail of the cell wall building block’s pentapeptide moeity
  2. RNA synthesis is distrupted

3.

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7
Q

What is an ionophores?

A

A drug that enables, allows unctrolled movement of ions across the cell membrane.

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8
Q

Have killer nano tubes reached the market?

A

No

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9
Q

How is disruption of protein synthesis carried out?

Mention some drugs groups that does this:

A

By binding to ribosomes and inhibiting different stages of the translation process

  • Aminoglycosides (30S unit in a way that mRNA is hindered)
  • Tetracyclines (30S unit -in a way that it inhibits tRNA from binding)
  • Chloramphenicol (Asite of the 50S subunit inhibit movement along mRNA)
  • Macrolides (50S unit)
  • Lincoasmides
  • Streptogramins
  • Oxazolidinones - prevents interaction between the 50unit and the 30unit
  • Pleuromutilins
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10
Q

Bacterial ribosomes is made up out of subunits, how many?

A

70S = 30S and 50S

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11
Q

What is an example of an aminoglycosides

A

Streptomycin

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12
Q

Aminoglycosides are bactericidal, true of false?

A

True

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13
Q

What are AMEs

A

Aminoglycoside modifying enzymes, weakens the Aminoglycoside affinity to the binding site of the 30S in ribosomes

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14
Q

Resistance against aminoglycosides

A
  • Structural changes in the outer membrane of gram negative bacteria
  • Efflux pump
  • Membrane proteases
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15
Q

Agents that act on nucleic acid transcription

A
  • Quinolones and fluoroquinolones
  • Spiropyrimidinetriones
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16
Q

Antibodies

A
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17
Q

Drug resistance

A
  • by mutation
  • by genetic transfer
  • ## Other factors affecting drugs resistance
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18
Q

What is MRSA

A

Bacterial that has developed a resistance to B-lactam resistant enzymes. This is due to mutations in their transpeptidase enzyme.

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19
Q

What are the qualities of good broad spectrum penicillins?

A

Broad spectrum penicillins must be able to target gram negative bacteria aswell. They should therefor be able to:

  • They must cross the outer membrane of gram negative bacteria
  • Not be suseptible to B-lactamase (steric sheild)
  • Has a high affinity to transpeptidase enzyme
  • Has a low rate of being pumped out of the bacterial cell, specially important for gram negative bacteria.
20
Q

What are three b-lactamase resistant penicillins?

A
  • Meticillin
  • Nafcillin
  • Oxacillin
21
Q

What side chain variations was tested in order to find broad spectrum drugs? and what was their effect

A
  • Hydrophilic side chains in alfa position
22
Q

What are good side chains for targeting G-negative bacteria

A
  • Hydrophilic side chain. This is because of the porins, in able to pass the porins the size, structure and charge are essential.
    Negatively charged side chains, hydrophobic and large are BAD for the drugs ability to pass the outer lipopolysaccharide membrane.
  • Good hydrophilic groups are (NH2, OH, CO2H)
  • The hydrophilic group should be in the alfa position to the carbonyl group of the side chain, in other words close.
23
Q

What kind of drug is sulfanomide? How does it work?

A

Antimetabolite.

Competative inhibitor of an enzyme that catalyzes production of tetrahydrofolate. Tetrahydrofolate is a cofactor in the synthesis of pyrimidine nucleic acid, which is important in DNA synthesis.

24
Q

What is important in the structure of analogues of sulphonamides?

A
  • Para-amino group is important for activity. R1 must be H.
  • R1= acyl is accetable since it can be metabolitzed in the body
  • Aromatic ring and sulphonamide is essential.
  • Sulphonamide and amino group must be directly attached to the aromatic ring
  • Aromaric ring must be in para position only! Due to steric reasons.
  • Sulphonamide nitrogen must be primary or secondary only. This is due to its need to be HBD.
  • R2 is the only possible site that can be varied.
25
Q

What is special for a sulphonamide prodrug?

A

R1 can be an acyl ==> metabolized into anactive sulphonamide.

26
Q

What is an bacteriostatic drug?

A

An agent that inhibits cell growth. Ex prontosil or sulfadoxine

27
Q

What is an bactericidal drug?

A

An agent that kills the bacterial cell, can be done through cell lysis. Ex Penicillin.

28
Q

Why is sulfadoxine and an other sulphonamides given to ADIS patient to treat bacterial infections?

A

Since sulfadoxine is an bacteriostatic drug it rely on a healthy imune system.

29
Q

How does sulphonamides inhibit dihydropteroate synthetase?

A

Mimic PAPA. Once bound it prevents PAPA to bind.

30
Q

Why is sulphanoamides not toxic to humans?

A

Since tetrahydrofolate is necessary for humans too it could be belived that sulphanomaides are toxic to humans. This is not the case since tetrahydrofolate is synthesised without dihydroperoate synthetase, instead it is formed from folic acid.

Bacteria have a susceptible enzyme that is not present in mamalians. Bacteria lack the transport protein that would allow them to transport folic acid across their cell membrane.

31
Q

Why is trimethoprim (antimetabolite) not toxic to humans?

A

Trimethoprim is not toxic to humans eventhrough they inhibit an enzyme that is excisting in human cells aswell and causes distruptived DNA sysnthesis ==> blocks cell division. The reason is that mutations over many million years have resultade in the enzymes in human and bacteria to have structural differances. Trimethoprim is 100000 times more active against the bacterial enzyme

32
Q

Give one example of synergism of penicillins with other drugs

A

Synergism = drug enchances the activity of another drug.

Probenecid, a drug that slows down the rate at which penicillin is excreted by competing with the ecretion mechanism. Competes with the binding of albumin (a protein in the blood, increases excretion). This increases level of penicillin in the blood ==> increases activity

33
Q

What is cephalosoprins derived from?

A

A fungus in the 1940.

34
Q

How does cephalosporin differ from penicillin?

A

It has a six membered dihydrothiazine.

It is not so potent as penicilline. More selective towards bacteria.

35
Q

What are two pros about cephalosporin?

A
  • Greater resistance towards acid hydrolysis and B-lactamase attacks
  • Less likely to cause allergic reactions
36
Q

Structural importance of celphalosporins

A
  • B-lactam ring within the bicyclic system
  • Ionized carboxylate in position 4
  • acylamino side chain in position 7
  • acetyloxy group in position 3 is a good LG, important in inhibition mechanism
37
Q

Possible possitions where modification can be made on cephalosporin

A
  • variation of 7 ACA
  • Acetyloxy side chain in position 3
  • Extra substitution at carbon 7
38
Q

What is one example of a carbapenems

A

Thienamycin

39
Q

What is special with thienamycin?

A
  • Missing a sulfur atom and acylamino side chain
  • Opposite sterochemistry to penicillin
40
Q

What does carbapenems and penicillin and cephalosporins have in common?

A

All has a B-lactam ring

41
Q

B-lactamase inhibitors, what are their function and give one example.

A

A way to inhibit the enzyme B-lactamase and in that way increase the activity of B-lactam containing rings. Results in low levels of the drugs.

  • Clavanic acid
42
Q

How are antibacterial agents that impairs proteins synthesis working? Why are they not dangerous?

A

They bind to ribsosomes and inhibiting different stages of the translation process.

They are not dangerous due to different difusionrates through the cell barrier of bacterial versus mammalian cells

43
Q

What are tetracyclines?

A

Bacteriostatic antibiotics

-Binds to bacterial ribosomes and prevent aminoacyl tRNA from binding. This stops translation and protein release

44
Q

What is chloramphenicol?

A

Similarly to tetracyclines it inhibits translation.

Chloramphenicol binds to the Asite of the 50S subunit, inhibiting the movement of ribosomes along mRNA. OH interacts with potasium and benzoring is important in Pi-Pi stacking.

45
Q

What does quinolones and fluoroquinolones do? Give some examples.

A

Inhibit replication and transcription of bacterial DNA by stabilizing the complex formed between DNA and topoismerases.

Nalidixic acid
Enoxacin
Ciprofloxacin

46
Q

What does Rifamycins do?

A

Inhibit Gram-positive bacteria and works by binding non-covalently to DNA-dependent RNA polymerase and by that inhibiting the start of RNA synthesis.

The drug binds to a peptide chain that doesn’t excist in human cells.

KOKN01 - Medicinal chemistry (12 decks)

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