Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

Antimicrobial compound deel II > Antibiotics targeting energy metabolism > Flashcards

Antibiotics targeting energy metabolism Flashcards

1
Q

Current treatment tuberculosis

A
  • Isoniazid
  • Ethoniamide
  • Pyrazinamide
  • Rifampin
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

New antibiotics for tuberculosis should:

A
  • Have rapid reaction
  • Be selective to kill bacteria (not patients)
  • Bioavailability intermittent treatment
  • Active on (almost) all individuals in all bacterial populations
  • In a bacterial population, bacterias different (but genotype can be the same)
  • Specific, well understood mechanism of action
  • Synergistic action in drug conditions
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

Working mechanism Isoniazid

A
  • Interfere with cell enveloppe
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Rifampin (fluorquinolones/ Aminoglycoside)

A

Back up drugs

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

Potential target mycobacteria tuberculosis?

A
  • Proton motive force
  • Complexes of respiratory chain (use proton motive force)
  • ATP synthase
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Phenothiazines: (inhibitor proton motive force)

A
  • Interfere with membrane functions
  • Ineterfere with oxygen consumption
  • Block Type II NADH > But bacteria will than use type I to survive
  • Change redox state of respiratory chain
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Clofazimine (NADH dehydrogenase inhibitor)

A

Same target as phenothiazines:
Interferes with membrane functions
- Its a repurpuse drug for M. Leprae
- Promising in combination therapy against tuberculosis
- Accepts e- from NADH type II and transfers them to oxygen&raquo_space; Create peroxide (ROS > kills bacteria)
- In normal essay you will miss this drug because is causes only 10-20% of inhibition.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Imidazopyridines: Cytochrome bc1 complex inhibition:

A
  • Cytochrome bc1 inhibition
  • bc1 is important for growth
  • Found by large screening and slowly improved last years
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

DARQ (diarylquinolines)

A
  • ATP synthase as target:
  • Prevents growth of M. tuberculosis
  • Impact biochemical pathway
  • Impact on bacterial growth
  • Impact cellular metabolite
  • Approval drug of last resort against MDR-tuberculosis. In phase II no serious side effects.
  • Promising new antibiotic :
    > Strongly active as drug target (Low [drug] can inhibit) : IC50 < 10 nM
    > Strongly active against M. tuberculosis
    > Sensitivity correlated with point mutation in ATP synthase. Stronly inhibit mycobacterial ATP synthesis. Is a strong argumentation that it was a target.
    > Acceptable for human volunteers
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Two types of NADH dehydrogenase (target)

A

Type I: Complex in mitochondria and homologous enzymes in bacteria
&laquo_space;Also target anti-cancer drugs
Type II: Found in microorganism (bacteria/yeast) : Has massive side effects but is a target for antibacterial drugs.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

Repurpuse drug

A

Drug proved for another disease

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Cytochrme bc1 complex inhibition

A
  • Not in our body
  • Kown as anti-parasitic drugs
    Bc1: Important for growth > Needs to be validated as target.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

Imidazopyridines against tuberculosis ontdekking

A
  • Make resistance mustations : One difference with wild type was a point mutation in bc1.
  • Offered more of target to the bacteria (up-regulation) > sensitivity was decreased
  • Did functional assay > Cellular ATP levels went down > So action imidazopyrine is related to energy metabolism
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

Cyt Bc1 as target needs validation

A
  • Maybe the point mutation makes cytbc1 more active and the real target is somewhere else
  • Need binding information
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

ATP synthase as target

A
  • Strange target because we use it ourselfs in mitochondrien. And bacteria don’t need it, they can grow without.
  • But DARQ is very specific, so low effect to human mitochondria
    DARQ: Slowly inhibits mycobacterial ATP synthesis
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

DARQ binding experiment:

A
  • DARQ binds ATP synthase: Find binding partners.
  • Two proteins identified > Strongly indication that it is the target
    ATP synthase subunits identified as DARQ binding partners.
17
Q

DARQ activity test

A

DARQ bind ATP synthase

  • Overexpression system for tuberculose: ATP synthase lacking
  • Sensivity correlated with point mutation in ATP synthase.
18
Q

Dormant bacteria

A 
Same genome as bacteria that are killed but these ones will survive. We don't know how.
Maybe:
- Down regulate their metabolism
- Inert to most antibiotics
- Low metabolic activity
- Maybe survive chemotherapy
19
Q

Biggest advantage of drug blocking energy synthase metabolism

A
  • These kill also dormant bacteria

Dormant bacteria are biggest challenge of antibiotics.

20
Q

Why the delay in energy metabolism inhibitors?

A
  • You see the first days no killing, this is why their working is underestimate.
    &laquo_space;This because the ATP level need to go down under a certain [] level before it will effect the bacteria.
  • But after three weeks lots of killing
21
Q

How do bacteria survive the first three weeks after energy synthase inhibitors

A
  • Upregulation of ATP syntheses
  • Upregulation dormancy response and don’t need much ATP anymore
  • Upregulate: Alternative energy pathways (cytochrome B)
  • Downregulation: Biosynthesis pathways (DNA, proteins, lipids)
22
Q

How does M. tuberculosis respond to blocking energy metabolism?

A
  • Transcriptosome, proteasome response
  • Observe level of target protein, pathway, metabolites and whole bacteria
  • Upregulation of ATP synthese > Upregulation of dormancy response.
23
Q

Influence energy source:

A
  • Tested sensitive for ATP syntheses
  • Do they use gluocose of fatty acids?
    > Kill was stronger with fatty acids as only energy source
    > M. tuberculosis can use human fatty acids as human energy source
    > When you knock out these sources, is dependent for working of ATP synthase inhibitors
24
Q

Underestimate working of ATP synthase inhibitors

A
  • Bacteria used other sources than ATP synthase
  • Work after three weeks
  • We use ATP synthase ourself
  • Bacteria don’t need ATP synthase to survive
25
Q

Problem tuberculosis now a days:

A
  • New drugs needed: 6 months antibiotic cocktail
  • Increasing resistance strains
  • 2-3 miljoen dead/year
26
Q

Proton motive force:

A
  • Pyrazinamide: Front line drug
    But target not known.
    Act on proton motive force not it’s main action.
  • Prodrug&raquo_space; Pyrazinoic acid [] high at infection site.

Mechanism:

  • Decrease membrane potential in M. tuberculosis
  • Also proton motive force in our mitochondrien.
27
Q

NADH dehydrogenase as target (Proton motive force)

A
  • Phenothiazines

- Clofazimide

Antimicrobial compound deel II (12 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions