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Antimicrobial compound deel II > Inhibition Cell wall syntheses and division in E.coli > Flashcards

Inhibition Cell wall syntheses and division in E.coli Flashcards

1
Q

Inhibitors cell wall

A 
Penicillin
Cephalosporins
Carbapenem
Monobactam
Glycopeptides
Lipopeptides
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2
Q

Inhibitors RNA / Protein synthesis

A 
Rifamycin
Aminoglycoside
Tetracyclines 
Macrolides
Chloramphenicol
Lincosamides
Mupirocin
Streptogramin
Oxazolidinones
Pleuromutilins
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3
Q

Cell division E.coli

A

Elongation&raquo_space; Z-ring formation&raquo_space; Divisome assembly&raquo_space; Constriction&raquo_space; Dell division
All steps can be targeted

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4
Q

Function peptidoglycan layer

And target

A

Gives strengt to bacterial wall
Mesh network of sugar and peptides
» Peptidoglycan down > Not a good shape and bacteria will die

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5
Q

Trans glycosylation

A

Bind sugars in long strand

PBP catalyse this reaction

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6
Q

Transpeptidation

A

Bind neighbour sugars with peptide bonds

PBP catalyse this reaction

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7
Q

Penicillin

A

Competition reaction: With D-ALA:

Binds in pocket region of transpeptidation reaction takes place > Breaks bond > Inhibit elongation

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8
Q

Most important targets in periplasm because:

A

Membrane enzymes are interesting targets. They’re easy to reach

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9
Q

Derogation

A

Afbraak peptidoglycan

Because it’s a dynamic proces

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10
Q

Elefheria terrae and its target

A
  • It’s a gramnegative bacterium against gram positive bacteria. Tested for antimicrobial activity:
  • Soil bacteria with Lipid II target peptidoglycan
  • Antibiotic can’t pass outer membrane
  • Couldn’t find resistance mechanism in bacteria
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11
Q

Peptidoglycan synthesis

2 models:

A

1.Takes place during elongation: Inserted in cylindrial wall
2. During division: Complete new synthesis of the cell poles
Different PBPs and different enzymes during this processes

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12
Q

MreB

A

Peripheral membrane protein at membrane in helical way:

  • Binds to enzymes that are important for peptidoglycan
  • Helps localising the elongasome
  • Without MreB: Structure will not form > Bacteria grows in spheres and die
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13
Q

FTS-Z and Z-ring

Indispensible cellular entity (onmisbaar voor de cel)

A

Formation of Z-ring in middle of elongated cell

  • The ring binds to the membrane via Zap A and FtsA
  • Polymerizes to form a contractile ring
  • GTP hydrolyzes : GTP couples to FtsZ monomers head to tail and forms a ring
    > The ring recruit division proteins (ZipA , FtsK)
    > The diameter decreases in this proces
    &raquo_space; After cell division you get disassembly (demontage)
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14
Q

Membrane protein FTS-Q in biogenesis E.coli:
Onderzocht by site specific photo crosslinking.
In a study of interactions of proteins.

A
  • Membrane protein with only one transmembrane segment.

Involved in cell division:

  • Best protein in biogenesis
  • Connects all major players: Alle major players must work together otherwise it won’t work.
  • Recruits all proteins to division site
  • Interacts with FTS-b and FTS-L &laquo_space;Drug targets
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15
Q

FTS-Z Advantages as target (5)

A
  • Target (Z-ring) is essential for bacteria
  • Broad range antibiotics
  • Catalytic activity when binding of ligands
  • Developing resistance is not easy
  • Structure is known
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16
Q

FTS-Z Disadvantages as target

A
  • Has a human homologue (Tubulin)
  • In cytosol (location isn’t great)
  • You need lots of this protein > So also need lots of antibiotics &laquo_space;It’s abundant (Z-ring used a-lot)
17
Q

FTS-Z inhibitors

Structure based design: Look to structure to inhibit

A

None has made market yet.
FTS-Z dimer interface:
- Analogue of GTP (morpholino-8GTP) replaces real GTP > Little bigger and inhibits polymerisation
- No normal Z-ring

18
Q

How FTS-Z knows were to form Z-ring

2 mechanisms

A
  1. Min system: Minc is polymerisation inhibitor and oscillates between poles.
    Low midcell [MinC] allows FTS-Z ring formation and inhibits FtsZ polymerisation

2 Nucleoid occlusion (opstopping): SlmA bound chromosome and inhibits FTS-Z.
Normal role of nucleoid occlusion prevent the genetic material in E.coli & SlimA also plays temporal role in organisation of division

19
Q

Binary fission process

A

Prokaryotic Cell division

  • Divide Cell in two equal parts
  • Also happens in our mitochondrien
20
Q

PBP3:

A

Is an transpeptidase crosslinks peptidoglycan polymers.

Essential for cell division

21
Q

Divisome and cell division

A

Recruitment of division proteins is hierarchical

  • FTS-Z is the first protein to localize the division site
  • FTS-Q : Connects all divisome proteins but function unknown.
22
Q

FTS-Q as target

A

When mutations in FTS-Q > Typical filamentous growth of cells > Cells stop dividing and grow as filaments

23
Q

FTS-Q as target Advantages

A
  • Target essential for survival
  • Catalytic activity / binding ligands
  • Broad range antibiotics
  • Hasn’t a close human homologue
  • Developing resistant isn’t easy
  • Toegankelijk for drugs: Subcellular location (Key interactions of FtsQ/FtsB/FtsL take place in periplasm)
  • Structure is known (crystal structure available)
  • Not abundant so low [drug] is enough
24
Q

FTS-Q as target Disadvantages

A
  • Catalytic activity / Binding of ligands
25
Q

Finding new antibiotics in soil

A
  • Culture soil bacteria in soil (mimic their environment)
  • Plate with chip: Sealed in platcid that is permeable to small nutrients > Nutrients can go soil in
  • But antibiotics that are produced can’t pass the soil and remain in the welsh
  • Test extracts for antimicrobial activity
26
Q

Elongasome

A

Complex that catalyzes peptidoglycan biosynthesis

&laquo_space;MreB helps localizing the elongasome

27
Q

Development FtsZ inhibitors:

In vitro assay/ In vivo screening:

A
  • In vitro: Screen for polymerisation & GTPase activity
  • In vivo screening: Compounds that affect membrane potential (indirect effect through decreased membrane association of FtsA)
    Screen for interaction ZipA, FtsA
    Look to effects on host > Toxicity and permeability of cel enveloppe
28
Q

FTSQ interactions

A

Upstream interactions take place in alpha domain (FtsK)

Downstream interactions take place in beta domain (FtsB/FtsL)

29
Q

Medicinal chemistry to find inhibitors for FtsQ

A
  • Screen small molecules that bind FtsQ
  • Test hits for inhibition
  • Optimize hits for inhibition cell division
  • Test efficacy of the molecules

Antimicrobial compound deel II (12 decks)

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