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Medical Microbiology > 11. Vancomycin resistance in enterococci and staphylococcus aureus > Flashcards

11. Vancomycin resistance in enterococci and staphylococcus aureus Flashcards

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1
Q

Why is vancomycin resistance a problem in MSSA?

A
  1. MRSA rates are low in the UK but vancomycin is still heavily used to treat MRSA.
  2. MSSA can be vancomycin-resistant without being methicillin-resistant.
  3. MRSA doesn’t often acquire vancomycin resistance
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2
Q

Is S. aureus gram positive or gram negative?

A

Gram positive

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3
Q

How can you tell a bacteria is gram positive?

A
  1. Through cell wall composition.
  2. Gram-positive bacteria have cross-links made of penta-glycine chains.
  3. This makes large gaps in the cell wall like honeycomb.
  4. The cell wall is full of holes and permeable but very thick.
  5. This makes the cell wall strong.
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4
Q

How can you tell a bacteria is gram negative?

A
  1. Through cell wall composition.
  2. in gram-negative bacteria, the cross-links are a direct link between DAP and the next D-ala.
  3. This creates a very dense and hard cell wall.
  4. It is hard to get molecules into the bacteria
  5. Also, they have two membranes.
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5
Q

Why is the bacterial cell wall cross-linking a good antibiotic target?

A
  1. It is a process that is unique to bacteria.
  2. The cell wall intermediates enter the periplasm for cell wall synthesis and they are more exposed.
  3. This makes selectively toxic antibiotics with targets that are easy to reach.
  4. This includes targets such as MurA and MurB, as well as PBPs.
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6
Q

What is an antibiotic that targets MurA in cell wall synthesis?

A

Fosfomycin

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7
Q

What is the committed reaction of cell wall synthesis?

A
  1. The conversion of glucose to glucosamine.
  2. It determines the rate of cell wall synthesis.
  3. If this reaction is stopped then you stop cell wall synthesis.
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8
Q

What are the 2 main steps in peptidoglycan synthesis once the precursors enter the periplasm?

A
  1. Transglycosylation
  2. Transpeptidase
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9
Q

What is the transglycosylation reaction in peptidoglycan synthesis?

A
  1. This is the joining of sugars to make the peptidoglycan chains.
  2. The penta peptide chains begin with a sugar and these are joined together to form the backbone of the cell wall.
  3. New sugars are just joined to the end of existing chains.
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10
Q

Why is the transglycosylation reaction not a good antibiotic target?

A
  1. All cells including human cells need to join sugars together.
  2. This is not a reaction specific to bacteria so the antibiotics are not selectively toxic and can damage other cells.
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11
Q

Why are the sugar chains in peptidoglycan cross-linked?

A

To add strength and rigidity to the cell wall.

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12
Q

What are Penicillin binding proteins?

A

Transpeptidase enzymes

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13
Q

What is the transpeptidase reaction in peptidoglycan synthesis?

A
  1. The pentapeptide chains end in 2 D-ala residues.
  2. This is what forms the cross-links in the cell wall.
  3. The bond between the 2 D-ala residues provides the bond energy to cross link the peptidoglycan chains.
  4. The bond between D-ala-D-ala is broken, and the energy released is used to form the new bond in the cross link.
  5. The terminal D-ala is no longer bonded to the chain and is lost.
  6. The cross-link forms between the 4th D-ala and the pentaglycine chains.
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14
Q

What can inhibit the transpeptidase reaction?

A
  1. ß-lactams
  2. This causes the cell wall to fall apart and the bacteria to die.
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15
Q

Why are the D-ala residues unusual?

A
  1. Usually amino acids are in the L isomer.
  2. It is almost exclusive to bacteria to have D isomer amino acids.
  3. This adds a selectivity to the antibiotics that target this.
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16
Q

Why can ß-lactams inhibit the transpeptidase reaction?

A
  1. Transpeptidases interact with D-ala-D-ala.
  2. ß-lactams look like D-ala-D-ala, so they bind to the transpeptidase active site and inhibit them.
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17
Q

What is the function of carboxypeptidases?

A
  1. They remove the terminal D-ala.
  2. This means there is no longer a pentapeptide chain that can form cross-links.
  3. This means carboxypeptidases control the amount of cross-linking in the cell wall.
  4. If there are lots of carboxypeptidases, there is less cross-linking.
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18
Q

What are some carboxypeptidases?

A

Penicillin Binding Proteins

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19
Q

Are carboxypeptidases essential for cell wall synthesis?

A
  1. No
  2. But without them bacteria make slightly weird cell walls.
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20
Q

What is Vancomycin?

A
  1. A glycopeptide.
  2. It is found naturally and is made by bacteria.
  3. It is a really big molecule that cannot fit through gram-negative porins, so it is used to treat gram-positive bacteria.
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21
Q

Why is Vancomycin used to treat gram-positive infections?

A
  1. It is big and cannot fit through the porins in the gram-negative membrane.
  2. Gram-positive bacteria have no outer membrane and an airy cell wall so it can fit through.
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22
Q

How does Vancomycin work?

A
  1. It binds directly to D-ala-D-ala.
  2. This prevents transpeptidases like PBPs from interacting with it.
  3. This causes the same effect as ß-lactams and prevents cross-links from forming and the cell wall falls apart and the cell dies.
  4. It binds to the substrate not the enzyme.
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23
Q

What is the difference between vancomycin and ß-lactams?

A
  1. Vancomycin binds to the substrate, D-ala-D-ala.
  2. ß-lactams bind to the enzymes, PBPs
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24
Q

What infections is vancomycin resistance important in?

A
  1. Enterococci infections.
  2. Enterococci infections weren’t a problem until Glycopepetide/vancomycin resistance emerged.
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25
Q

How are Enterococci infections caused?

A

They are gut bacteria so they get into places through faecal contamination.

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26
Q

How is Glycopeptide resistance caused?

A
  1. Resistance by target site modification.
  2. As the target isn’t an enzyme there isn’t a single mutation that can cause the modification needed.
  3. D-ala-D-ala is the target and needs to be modified. This is not genetically encoded, so it is mediated by enzymes.
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27
Q

What is the most common type of vancomycin resistance?

A

VanA mediated resistance.

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28
Q

What does vancomycin resistance normally also gives resistance to?

A
  1. Teicoplanin.
  2. This is another glycopeptide that is mainly used in the US.
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29
Q

Where is vancomycin VanA resistance encoded?

A
  1. On a transposon
  2. It can move between enterococci.
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30
Q

How did Vancomycin resistance evolve?

A
  1. To give resistance to the bacteria that produce vancomycin.
  2. This protects them from the antimicrobials they produce.
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31
Q

What shows that vancomycin resistance specifically evolved to protect bacteria from themselves?

A
  1. It is inducible by vancomycin.
  2. VanA is switched on in the presence of vancomycin.
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32
Q

What does VanA mediated vancomycin resistance do?

A
  1. It physically changes the structures of the cell wall so vancomycin cannot bind.
  2. The 2nd D-ala is switched for a D-lac.
  3. There are other Van genes that cause switches for other amino acids.
33
Q

What Van genes cause the most resistance?

A
  1. From the Van genes like VanA that are on plasmids.
  2. The Van genes that are inducible
  3. The chromosomal Van genes are specific to species and give low MICs.
34
Q

What is the genetic arrangement of the VanA system?

A
  1. It is a gene cassette of multiple genes as it is complicated to switch the amino acids.
    2.
35
Q

What genes are in the Van A system?

A
  1. vanR
  2. vanS
  3. vanH
  4. vanA
  5. vanX
  6. vanY
36
Q

What does D-ala ligase do?

A

It joins 2 D-ala residues together.

37
Q

What does VanX do?

A
  1. It is a dipeptidase that breaks down D-ala-D-ala.
  2. This prevents it from entering the cell wall synthesis pathway.
  3. It is a futile cycle in vancomycin resistant bacteria but it keeps the cell alive.
  4. It reduces the potential for D-ala-D-ala to enter the cell wall.
  5. It is the first step in vancomycin resistance.
38
Q

What does VanH do?

A

It makes D-lac from pyruvate.

39
Q

What does VanA do?

A

It joins D-lac to D-ala to make D-ala-D-lac.

40
Q

What adds D-ala-D-lac to the other cell wall precursors?

A
  1. An adding enzyme.
  2. It doesn’t know the difference between D-ala-D-ala and D-ala-D-lac.
  3. It just adds which ever is most abundant to the rest of the forming peptidoglycan.
41
Q

What does VanY do?

A
  1. It is a DD carboxypeptidase the removes the terminal D-ala.
  2. This prevents vancomycin from binding to D-ala-D-ala already in the cell before the VanA system is induced.
  3. This temporarily stops cross-linking.
42
Q

Why is the function of VanY important?

A
  1. The Vancomycin can bind to the D-ala-D-ala already in the cell wall
  2. Some D-ala-D-ala will still be made and make it into the cell wall.
  3. You cannot destroy the cell wall before you make a new one so you remove the terminal D-ala to prevent vancomycin binding.
  4. These terminal D-ala are quickly replaced with D-ala-D-lac to restore the cross-linking function.
  5. This pause is preferable to the permanent stop that vancomycin binding causes.
43
Q

How quickly does the composition of the cell wall change?

A

Within a generation

44
Q

Why don’t bacteria make D-ala-D-lac all the time if it has no impact on their survival?

A
  1. The transpeptidase treat D-ala-D-ala and D-ala-D-lac the same.
  2. It has no fitness cost.
  3. The bacteria don’t need to make D-ala-D-lac all the time so there is no point changing the normal.
  4. VanA is encoded on a plasmid so it is not universally expressed in enterococci.
45
Q

What does VanS so?

A
  1. It is a signal sensor.
  2. It senses and directly binds Vancomycin.
  3. VanS is phosphorylated in the presence of vancomycin to activate it.
  4. VanS then activates VanR by phosphorylation.
46
Q

What does VanR do?

A
  1. It is a response regulator and transcriptional activator.
  2. Once it is phosphorylated by VanS, VanR binds to the operon promoters and activates the expression of the other Van genes.
47
Q

Where was VanA resistance first discovered?

A
  1. In enterococci
  2. And enterococci were first found in pigs.
48
Q

Why are pigs linked to VanA mediated resistance in enterococci?

A
  1. Lots of pigs have been fed Avoparcin as a growth promoter.
  2. Avoparcin is another glycopeptide.
  3. This has caused the selection of VanA-producing enterococci in pigs.
  4. Avoparcin use as a growth promoter in now banned in Europe.
49
Q

Could VanA-mediated resistance in pigs have caused vancomycin in humans?

A
  1. Possibly but there are very weak links.
  2. It is more likely the VanA plasmid could have jumped from pigs enterococci to human enterococci but not the bacteria themselves.
50
Q

What group of enterococci mostly infect humans?

A
  1. Group A1
  2. These also infect pets, but not usually farm animals.
51
Q

What group of enterococci mostly infects farm animals?

A
  1. A2
  2. These infect farm animals like pigs.
  3. They can cause a few human infections, but it is uncommon.
52
Q

What has caused the increase in vancomycin enterococci infections?

A
  1. The use of Vancomycin to treat MRSA.
  2. This has led to the selection of VanA expressing Enterococci in the human gut.
53
Q

What has caused the selection of the VanA gene cassette and it transfer to humans?

A
  1. VanA was selected for in pigs by using glycopeptides as growth promoters.
  2. Using drugs in animals before they are used in humans is a bad idea as it causes resistance mechanisms to develop in the environment.
  3. These can then transfer into human infections.
54
Q

Why is S.aureus a more important pathogen then enterococci?

A

It causes more deaths and more infections.

55
Q

What is vancomycin is very important for treating?

A

MRSA

56
Q

How could MRSA and other S.aureus gain vancomycin resistance?

A
  1. S. aureus is very similar to enterococci so it was thought they would easily obtain VanA.
  2. This has been done in a lab but not observed very much in nature.
  3. We don’t know why really this hasn’t happened, but it’s mostly due to the cell wall of S. aureus not tolerating the change.
57
Q

What is GISA?

A

Glycopeptide intermediate resistance

58
Q

How did Glycopeptide intermediate resistance come about?

A
  1. It comes from the Americans.
  2. Americans use a lot of glycopeptides in farming so they are worried about it being linked to human infection. This is banned in Europe.
  3. They changed the breakpoints so the definition of resistance is higher in America than in the rest of the world.
  4. It then became a compromise with the Americans to call the infection between the 2 definitions kind or resistant or intermediate resistant.
  5. This creates a scale of resistance with most of these infections on the borderline of resistance.
59
Q

How was the GISA scale adopted by the rest of the world?

A
  1. The American called infections with an MIC of 8-16 intermediately resistant and >32 truly resistant.
  2. The French agreed, and then the rest of Europe adopted the scale.
60
Q

What causes GISA?

A
  1. Not VanA mediated
  2. Caused by altering the cell wall.
61
Q

How was vancomycin intermediate resistance visualised?

A
  1. Using colony counts with different concentrations of vancomycin and then measuring how many bacteria are still alive after a period of time.
  2. With MSSA or MRSA the live bacteria drops very quickly.
  3. Mu50 was an MRSA strain in Japan that was considered vancomycin-resistant, and the bacteria stayed alive and population high for a while and then slowly decline.
62
Q

How was heterogeneous vancomycin intermediate resistance discovered?

A
  1. Using the same colony counting as the Mu50 analysis.
  2. Mu3 is another MRSA strain from Japan, in which the population declines quickly and continues to decline but at a slightly slower rate.
  3. There was no phenotypic difference in the cells in the population, but some were surviving, and some were resistant to treatment.
  4. This is heterogenous resistance or hVISA. It is not considered true resistance
63
Q

Is hVISA clinically relevant?

A
  1. Yes - kind of
  2. As some of the population survive treatment they cause treatment failure and can cause complications.
  3. It is hard to know the true impact of hVISA.
  4. Usually, the biggest issue in patients is that getting high concentrations of antibiotics is hard.
64
Q

Why are VISA rare?

A
  1. These strains have vancomycin resistance at a huge fitness cost.
  2. This means they don’t grow very well.
  3. They are not very transmissible or cause long term disease.
65
Q

Why are hVISAs more common then VISAs?

A
  1. They exist in a goldilocks zone.
  2. They are not as resistant or damaging as VISAs.
  3. But they are fitter and more transmissible.
  4. They still have some fitness cost but appear more often.
  5. They mainly affect people who are in hospital long term.
66
Q

What is the key in hVISAs?

A

The individual bacteria is not resistant but the population is.

67
Q

How do VISAs like Mu50 resist vancomycin treatment?

A
  1. They make their cell wall thicker so it acts like a sponge and absorbs all the vancomycin by binding it to D-ala-D-ala.
  2. Once the vancomycin is bound it is stuck there.
  3. The thicker cell wall means you can absorb all the vancomycin and still have some D-ala-D-ala left to form the cross links in the cell wall.
  4. This means the cell can survive vancomycin treatment and raise the MIC above the intermediate resistance break point.
68
Q

How do hVISAs like Mu3 resist vancomycin treatment?

A
  1. Mu3 makes more cell wall to absorb the vancomycin.
  2. It binds to the D-ala-D-ala but doesn’t leave enough spare to form cross links.
  3. This means there is not a big shift in MIC to cause true resistance.
  4. However some of the Mu3 bacteria absorb lots of the vancomycin and take one for the team by dying and taking the vancomycin with it.
  5. The other cells in the population can survive
  6. This is the heterogeneous effect
69
Q

How does the VISAs/hVISAs produce more cell wall?

A
  1. There is an increase in the glucose-to-glucosamine reaction to form more precursors.
  2. This increases the cell wall synthesis rate.
  3. There is also a loss of autolysins and carboxypeptidases to prevent cell wall break down.
70
Q

What causes the increase in cell wall production in VISAs?

A
  1. Large amounts of genetic changes.
  2. There needs to be multiple mutations in multiple regulators.
  3. This is a multi-step and complicated process.
  4. This means a hVISA like Mu3 can easily become a VISA like Mu50 by accumulating mutations.
71
Q

What is the disadvantage to the extra production of cell wall in VISAs?

A
  1. It comes with a large fitness cost.
  2. This is because making cell walls is very energy intensive.
  3. This means that they don’t have enough energy to divide or cause disease effectively.
72
Q

Why does producing lots of cell wall take lots of energy?

A
  1. Lots of raw materials
  2. Lots of bond formation
73
Q

Where was the 1st case of true vancomycin resistance in S. aureus?

A

In the USA.

74
Q

Why was the 1st case of true vancomycin resistance in S. aureus in the USA?

A

Due to their overuse of glycopeptides as growth promoters in farming.

75
Q

How did true vancomycin resistance in S. aureus occur?

A
  1. 1st found in a diabetic wound.
  2. Conjugation between enterococci and a S. aureus causing the transfer of the VanA plasmid.
  3. This is a very rare event.
76
Q

Why is true vancomycin resistance rare in S. aureus?

A
  1. The resistance is mediated by VanA.
  2. The D-ala-D-lac cross-linking doesn’t work as well in S. aureus.
  3. So the resistance mechanism is almost as damaging as the drug itself.
77
Q

When will vancomycin resistance in S. aureus be a serious problem?

A

When S. aureus adapts to to make D-ala-D-lac more efficient and make a functioning cell wall with it.

78
Q

Why are gram positive easy to find treatment for?

A

It is easy to get molecules into them, so it is easy to find alternative treatments.

79
Q

Why are some bacteria intrinsically vancomycin resistant?

A
  1. They produce vancomycin as a means of competition.
  2. This means they need to protect themselves.
  3. This was the VanA gene cassette.

Medical Microbiology (16 decks)

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