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Kirstys Flashcards > PMB: Antibiotics 5&6 > Flashcards

PMB: Antibiotics 5&6 Flashcards

1
Q
  1. Where do antibiotics typically come from?
  2. What can they be used for and why?
    3.
A
  1. AB typically occur naturally
  2. They can be used to treat infectious disease due to being selecive for bacteria
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2
Q

In order for an AB to be effective what properties must it have?

A

It must have at least one of:

  1. The AB target should be lacking in host tissue
  2. The AB should concentrate in the bacterial cells

Ideally both would be better

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3
Q

What is the mode of action of ABs?

A
  • They bind to specific target enzymes or molecules within the bacterial cell
  • They work by inhibting key macromolecules
  • Different ABs have different target sites e.g.:
    • Nucleic acids synthesis - RNA or DNA
    • Protein synthesis - often translation apperatus
    • Peptidoglycan synthesis - affects development of cell wall
  • No secondary effects
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4
Q

Describe the basics ways in which an AB can inhibit nucleic acid synthesis (RNA and DNA)

A
  • Can either block nucleotide synthesis
  • Or inhibit enzymes catalysing synthesis:
    • DNA Gyrase
    • RNA polymerase
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5
Q

What are examples of steps blocked in the pathway for nucleotide synthesis? What are the enzymes involed?

A
  • Conversion of PABA to DHPA (sulphonamides)
  • Conversion of DHFA to THFA (trimethoprim)
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6
Q
  1. What is THFA
  2. what does it do?
  3. What 2 ABs can be used to inhibits its production?
  4. Synthetic or natural ABs?
A
  1. It is tetrahydrofolate
  2. Precusor for purine and pyrimidine synthesis
  3. Sulphonamide and trimethoprim
  4. Synthetic
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7
Q

How does sulphonamide work?

A

It is an analogue for p-amino benzoic acid. It acts as an alternative substrate to DHPA (dihydropteroate synthase) and blocks the enzyme

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8
Q

How does Trimethoprim work?

A

It is an analogue for Dihydrofolate (DHFA). It binds to the enzyme Dihydrofolate reductase and inhibits the enzyme and therefore synthesis of THFA

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9
Q

What is trimethoprim used for?

A
  • used to treat uncomplicated UTIs from gram negative bacterias
  • Used to treat inflammation of kidney Pyelonephritis and inflammation of prostate gland (prostatitis)
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10
Q

Describe bacteria DNA in relation to structure and requirements for DNA replication

A

Bacteria DNA is cirulcar and double stranded

It is normally a supercoiled structure (takes

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11
Q

Explain the puropse of DNA gyrase?

What would happen in the absence of it?

A

Its function is to relax supercoiling of DNA by breaking phosphodiester bonds in both strands. These bonds will reform after relaxing.

If there is no DNA gyrase there is no DNA replication, therefore no cell division

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12
Q

What AB inhibit DNA gyrase?

A
  • Quinolone ABs e.g. Naladixic acid
  • Second generation Quinolone ABs e.g. ciprofloxacin - broader spectrum of activity
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13
Q

What is the function of RNA polymerase?

A
  • DNA transcribed to RNA
  • RNA translated to protein
  • RNA catalaysed transcription
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14
Q

What AB inhibit RNA polymerase?

A

Rifamycin e.g. rifampicin

RIfampicin - used to treat gram positive bacterial infections

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15
Q

What are the 2 main mechanisms which AB can block protein synthesis?

A

Inhibit elongation or initiation

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16
Q

Give a general overview of transcription

A

30s binds to first set of codons. The tRNA anticodon binds to the condon on the DNA strand. The 50s unit binds to 30s unit. Another tRNA molecule binds it anticodons to the next codon. The 2 AA form a peptide bond and the first tRNA keaves. The 30s and 50s complex move along to next codon and the next tRNA comes

17
Q

What groups of ABs exist which inhibits protein synthesis?

A

Aminoglycosides

Tetracyclines

Macrolides

Amphenicols

Oxazolidinones

18
Q

What are aminoglycosides subdivided according too?

Give examples

A

According to mode of action and structutre

e.g. streptomycine or spectinomycin

19
Q

Describe how streptomycin works

A
  • Has bacteriocial activity
  • Binds irreversibiy to a single site on the 30s ribosomal subunit
  • Binding blocks the formation of the 30s ribossomal initiation complex needed to start protein synthesis
20
Q

Describe the mode of action of spectinomycin

A
  • Reversible and bacteriostatic
  • Also binds at 30s ribosmomal site
  • It inhibits the elongation process by inhibiting the normal translocation (movement) of the ribosome along the mRNA molecule
21
Q

Describe mode of action of gentomycin

A
  • Bacteriscidal
  • Acts at many different sites on the ribosome
  • Prevents elongation phase by inhibiting binding of elongation factor (EF-G) to ribosome
  • Tobramycine and neomycin act in similar ways
  • Used to treat grame -ve infections
22
Q

Describe mode of action of tetra cycline

What are the problems and how are these overcome

A
  • Bacteriostatic antibiotics
  • Broad spectrum of activities
  • Limited use now due to spread of resistance
  • Still used for some obligate intracellular pathogens
    • e.g. Chlamydia trachomatis
  • Bind reversibly to site in 30S subunit
  • Disrupt codon-anticodon interaction between mRNA and tRNA
  • Blocks tRNA binding to ribosome - stopping synthesis
  • Problems with resistance
  • Overcome by developing glycylcyclines which in act in same way e.g. tigecycline
23
Q

How to macrolides work?

A

They bind to a specific site on the 50s ribsosomal subunit nd cause premature dissosociation of tRNA during protein synthesis

24
Q

What can macrolides be used to treat?

What type of AB are they?

What are examples

A
  1. Used ti treat gram positive cocci
  2. Bacteriostatic
  3. Erthromycin and clarithromycin
25
Q

How do amphenicols work?

A

They are bacteriostatic

They bind to a specific binding site on the 50s ribosomal subunit and inhibit the enzyme peptidyl transferase. This is an enzyme which catalyses peptide bond formation

26
Q

What is an example of amphenicols?

What are do they treat?

A

Chloramphenicol

Used in eyed drops and effective against E.coli, S.Aureus, Steptoccus phenumonia

Broad spectru

27
Q

How do oxazolidinones work?

A

Bind to 50s ribosomal subunit and inhibit the formation of the 70s initation complex

28
Q

What are oxazolidinones used for?

Examples

A

Used specifically for Gram positive cocci

VRE, MRSA

29
Q

Why is peptidoglycan synthesis a good target for ABs?

A

Almost all bacterial cells contain peptidoglycan, where as human cells do not. Peptidoglycan gives the bacterial cells their strength. Inhibitation of peptidogylcan synthesis leaves the cells subseptible to cell lysis

30
Q

What step are involved in peptidoglycan synthesis?

A

There are 3 main stages:

  1. Fist step takes place in the cytoplasm where UDP-NAMA-pentapeptide precursors are prepared
  2. Second stage involves transmembrane movement of the precursor (and addition of NAG) to the outer membrane surfacce
  3. The last stage involves the incopperation of NAG-NAMA-tetrapeptide into the growing peptidolgycan
31
Q

Give an example of a stage 1 inhibitor and its mechanism of action

What is it used to treat?

A

Fosfomycin is a PEP analogue

  • It it inhibits the intermediayte UDP-NAG-enoylpyruvate by the inactivation of pyruval transferase
  • It is used to treat UTIs
32
Q

Give another example of a stage 1 inhibitor and its mechanism of action

Used for?

A
  • D-cycloserine is an analogue for D-alanine
  • It works by inhibting the synthesis of D-alanyl-D-alanine and hence UDP-NAMA-pentapeptide
  • It does this by ihbition of alanine racemase and D-alanyl-D-alanine synthase
  • Second line treatment for TB
33
Q

What is an example of a stage 2 inhibitor and its mechanism of action?

Used for?

A
  • Bacitracin is a cyclic peptide effective at blocking the membrane tansportation step in the synthesis
  • It binds to the lipid carrier undecaprenyl pyrophosphate and this binding prevents enzymatic dephosphorylation of the lipid carrier to monophosphate form.
  • Dephosphorylation is essential for carrier to bind UDP-NAMA-pentapepeptide
  • Commonly used with neomycin and polymyxin B for skin or eye infections
34
Q

Give an example of a inhibitor of the last stage and its mechanism of action

Uses

A
  • Glycopeptides
  • Example is vancomycin
  • Interferes with the transglycosylation process
  • Transglycosylation is process causing insertion of NAG-NAMA-pentapeptide unit into growing peptidoglycan chain.
  • Vancomycin blocks transglycosylation process
  • Binds to both the incoming unit and the exposed D-alanyl-D-alanine end of growing peptidoglycan chain
  • Toxicity means it is a last resort for serious infections caused by Gram positive species.
  • Televancin, a new lipoglycopeptide derivative, acts in the same way
  • also causes membrane depolarisation.
35
Q

Discuss B-lactams

A
  • Include the penicillin (penams) and cephalosporin (cephems) antibiotics
  • Most widely prescribed group of antibiotics
  • Effective against both Gram positive and Gram negative species
  • Inhibit transpeptidation reaction
  • Final stage of peptidoglycan synthesis
  • Structural analogues of acyl-D-alanyl-D-alanine portion of the precursor peptide
  • Transpeptidase enzyme recognises antibiotic instead of normal substrate
  • The β-lactam ring is cleaved
  • A covalent antibiotic-enzyme intermediate is formed – this is inactive

Kirstys Flashcards (116 decks)

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