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Antimicrobial compound deel II > Host directed therapy > Flashcards

Host directed therapy Flashcards

1
Q

Nosocomial infection

A

Infection you acquire in hospital

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2
Q

Drug resistant infections

A

Resistance to first line antbiotics

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3
Q

Goal host directed therapy:

A

Prevent replication of pathogen > Prevent death of host

- Killing the pathogen is not always the main goal

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4
Q

Challenges host directed therapy

A
  • Safety
  • Efficcacy: Have to be affecting against pathogen you fight against
  • Competing drugs
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5
Q

ED50/ TD50

A

Dose required to produced a (therapeutic-/toxic- effect) in 50% of the population

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6
Q

Therapeutic index

A

Toxic effect/ Efficiacy effect= How well works a drug

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7
Q

When host therapy used?

A
  • Viruses and intracellular bacteria (chlamydia)
  • Immune modulation to enhance or suppress response to a pathogen (inhibit cytokines)
  • Multi drug resistant pathogens > (resistance not expected)
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8
Q

How target the pathogen in host directed therapy?

A
  • Small molecules
  • Large biologicals (Antibodies)
  • Genetic engineering
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9
Q

Plerixafor

A

Against binding CXCR4

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10
Q

Maraviroc

A

Against binding CCR5

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11
Q

Example HIV: host therapy

A

limit infection and host cell death with small molecules

  • Block caspase I&raquo_space; No pyroptosis
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12
Q

Two types of infection virus

A
  • Successful infection

- Abortive infection (95%): CD4 cells that aren’t infected.

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13
Q

Pyroptosis in HIV infection

A

High inflammatory programmed cell death of CD4

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14
Q

Example mycobacterial infection ,

host therapy

A

Limitation of nutrients / dissemination with small molecules.

Not target bacteria directly but via host
- Prevent outgrow of blood vessels > Prevent granuloma growth in zebrafishes

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15
Q

Pazipanib: Anti mycobacterial

also anti-tumor

A

VEGF inhibitor

VEGF = Vascular Endothelial Growth Factor

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16
Q

Example Toll Like Receptor, host therapy

A

Immune modulation to enhance or suppress response to a pathogen with small molecules

17
Q

TLR: Function

A

Recognises pathogen associated molecular patterns
In endosome and at the surface.
Share the IRAK4 pathway

18
Q

Septic shock

A

Due to TLR4 that recognises LPS

Oplossing:
Block dimerisation of TLR4 < Doesn’t work for long treatment
No drug yet

19
Q

TLR as therapeutical target

A

TLR7&raquo_space;

Imiguimod&raquo_space; Against genital warts&raquo_space; Boosed immune system

20
Q

Example s. aureus infections, host therapy

A

Eradication of intracellular bacteria with large biologicals

Target small amount that are inside host cells (system effects) > Eradicate S. aureus out body with antibodies.

21
Q

ADC

A

Antibody drug conjugates: Antibody with drug > Bind receptor > Host caspase releasse drug > Cell killed

22
Q

AAC

A

Antibody Antibiotic conjugates: Antibody recognises pathogen.

Antibody binds bacteria > High concentration inside cell&raquo_space; Killing bacteria in cell

  • If only a antibioticum given > Works but still some bacteria survive
  • AAC: No bacteria alive anymore
23
Q

AAC pros

A
  1. High [antibiotic] at the infectious site
  2. AAC longer half life than normal antibioticum (normal antibioticum 4 hours)
  3. Works only on bacteria , normal antibioticum kills everything what looks like.
  4. Spares the commensal flora
24
Q

AAC cons

A
  1. Application for a limited numer of pathogens (only intracellular) &laquo_space;So doesn’t work against every pathogen
  2. Very expensive, more than normal antibiotics
  3. Intravenous delivery
25
Q

CRISPR

A

Genetic code in bacteria where they place virus DNA

It’s programmable : You give a copy of DNA you want to modify and put the system into a living cell.

26
Q

Bacteriophages

A

Place own genome into bacteria&raquo_space; Mostly the bacteria dies&raquo_space; Sometimes it survives and save a part of the virus DNA in their own genetic code called CRISPR&raquo_space; In CRIPR it’s stored till needed.

  • When virus attacks again > Bacterium quickly makes crRNA which bound mRNA of virus and makes it double RNA&raquo_space; Danger signal
27
Q

Protein Cas9

A

Scan bacterium inside for signs of the virus invader, compares every bit of DNA
When it finds virus it’s activated and cuts out the virus DNA making it useless&raquo_space; Protecting the bacteria against the virus attack
- Cas9 is very precise

28
Q

Example HIV in CRISPR

Gene editing

A

Curing by gene editing:
- Cut out HIV gene of patient cell and give to rat
> Inject CRISPR > Removes 50% of the virus from cells all over the body

  • Crystal therapy might cure HIV and other retroviruses
  • Alle viruses that hide inside the human DNA could be eradicted this way
29
Q

Cons: CRISPR in HIV therapy

A
  1. Need constantly target the virus with CRISPR, because virus mutates over time and can bind again
  2. It’s only activated when you have HIV, so not available as vaccin,
    Cas9 under death receptor
  3. It’s very specific on bases in DNA
  4. Can get cancer when it binds wrong
30
Q

Example Malaria in CRISPR

Prevent malaria by engineering the vector (musquitos) via large biomolecules and genetics.

A
  • The musquitos become immune for the parasite

- Cas9 binds where normally the plasmodium binds

31
Q

Normal malaria infection:

Plasmodium and malaria cycle

A

Plasmodium consists of single cells and veroorzaakt Malaria

Sporozoids into the skin > Hide for immune system > Become merozoids > multiple and burst into the blood stream
» Hide in membrane of infected cells , so immune system doesn’t recognize them

32
Q

Transgenic anopheles stehensi

A

Coexpression of single chain antibodies resist plasmodium development

33
Q

HIV cycle

A

HIV enters cell&raquo_space; Stimulate pyroptosis&raquo_space; Release of pro-inflammatory cytokines&raquo_space; Inflammation&raquo_space; Recruitment of healthy CD4 cells&raquo_space; Infection etc..

34
Q

Gene driving principle

A

Gene driving by gRNA and Cas9
- Guide RNA and Cas9 incorperated in DNA of plasmid were normally plasmodium binds
- Transfer ‘new’ sequence to native chormosome
- From heterogenous to homogenous
» Easy to transorm complete organisms

In malaria:
- 2 antibodies needed that recognise plasmodium
> Prevent replication and prevent spread of pathogen

Antimicrobial compound deel II (12 decks)

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