Antibiotics 2 Flashcards

1
Q

3 modes of AMR (antibiotic resistance)

A

Intrinsic resistance
Acquired resistance
Tolerance

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2
Q

Intrinsic resistance

A

Bacteria you’re looking at can’t be killed by that drug

e. g. bacteria lack target structure or possess an impermeable cell envelope
- Gram-negatives are intrinsically resistant against many penicillins

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3
Q

Acquired resistance

A

Renders a formally sensitive bacterium resistant
e.g. through spontaneous mutation
OR by picking up resistance determinants
(horizontal gene transfer)

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4
Q

Tolerance

A

Cells are temporarily in a physiological state that renders them ‘resistant’
- endospores, dormant cells or cells in biofilms
= not normally susceptible to antibiotics

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5
Q

4 main mechanisms of acquired AMR

A

Change the target

  • Spontaneous mutations (e.g. in enzymes)
  • Acquisition of alternative genes or pathways

Degrade the AB
-Via hydrolytic enzymes

Modify the AB

  • Modifying enzymes
    (e. g. acetyltransferases)

Export the AB
- Via active transporters

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6
Q

Changing the target

- 3 ways

A

Spontaneous point mutations

Acquisition of an alternative gene

Acquisition of an alternative biosynthetic pathway

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7
Q

Changing the target
- spontaneous point mutation
> example of AB and how they work

A

Quinolones e.g. Ciprofloxacin

Bind to GyrA subunit of DNA gyrase near where it would normally bind to DNA
-> inhibits DNA gyrase

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8
Q

Changing the target
- spontaneous point mutation
> resistance against Quinolones

A

Point mutation in QRDR region abolishes quinolone binding

-> gyrase is still active but now resistant

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9
Q

QRDR

A

Quinolone resistance determinant region

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10
Q

DNA gyrase

- how does it work?

A

2 subunits - GyrA and GyrB
slot into each other
-> slot around DNA
-> controls supercoiling

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11
Q

Point mutations

- transferal

A

Mutations now on chromosome
-> passed onto daughter cells

NOT normally transmitted horizontally between bacteria

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12
Q

Changing the target
- acquisition of an alternative gene
> example of an AB and how they work

A

Penicillin

Bind and irreversibly block transpeptidases (PBPs = penicillin binding proteins
- )

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13
Q

Changing the target
- acquisition of an alternative gene
> some forms of PBPs

A

Lower substrate affinity
-> less likely to bind penicillin and become inactivated
= resistance

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14
Q

Acquisition of an alternative gene
- MRSA
> what does it stand for?
> resistance

A

Methicillin Resistant Staphylococcus aureus

Possesses mecA gene
- encodes low-affinity PBP
= PBP2a

mecA is part of mobile genetic element - SCCmec
- can become v large + carry multiple resistance genes against different classes of AB

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15
Q

Acquisition of an alternative gene
- MRSA
> spread of mecA

A

As part of SCCmec

  • > can be readily passed between different staphylococci
  • > spread of resistance
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16
Q

Changing the target
- acquisition of an alternative biosynthetic pathway
> example of an AB and how it works

A

Vancomycin

Bonds to the terminal D-Ala-D-Ala of peptidoglycan precursors
-> inhibits transpeptidation

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17
Q

Acquisition of an alternative biosynthetic pathway

- Vancomycin resistance

A

Synthesis of alternative peptidoglycan precursors
- alternative ending to D-Ala-D-Ala

e.g. D-Ala-D-Lactate
Can’t be bound by vancomycin

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18
Q

Acquisition of an alternative biosynthetic pathway

- modification of D-Ala-D-Ala

A

Requires several genes to create an alternative biosynthesis pathway

  • synthesis of different peptides (vanH, vanA)
  • removal of regular precursors (vanX, vanY)
  • regulatory genes (vanR, vanS)
19
Q

Acquisition of an alternative biosynthetic pathway

- Vancomycin resistance spread

A

Encoded on mobile genetic elements

  • > can be passed between bacteria
  • > spread of resistance
20
Q

Acquisition of an alternative biosynthetic pathway
- VRE
> what is it?

A

= Vancomycin Resistant Enterococci

21
Q

Importance of vancomycin

A

Beta-lactams + vancomycin both target the cell wall
BUT resistance mechanisms are so different
that vancomycin is v useful in treating beta-lactam resistant infections (like MRSA)

22
Q

Degrading the antibiotic

  • example of AB used
  • process of resistance
A

Beta-lactam antibiotics
e.g. penicillins

Beta-lactamases

  • cleave the B-lactam ring between N + C
  • > inactivates the AB
23
Q

Degrading the antibiotic
- Extended spectrum beta-lactamases (ESBL)
> what are they?
> when are they mostly a problem?

A

Can target a wide range of beta-lactam ABs
- including the semi-synthetic derivatives that were previously beta-lactamase resistant

In E.coli = Gram-negative

24
Q

ESBL

- why are they not a problem in Gram- positives?

A

Most beta-lactamases are secreted into periplasm (where AB target is)
- Gram-positives have no periplasm

25
Q

Modifying the antibiotic

- example of AB and how it works

A

Aminoglycosides e.g. Kanamycin

Binds to 16S rRNA
-> inhibits protein synthesis

26
Q

Modifying the antibiotic

- Why no point mutations in 16S rRNA?

A

16S rRNA is too essential for functioning of ribosome
- bacteria would just die

Gene often present in several copies per genome
-> would have to mutate all copies before cell is resistant

27
Q

Modifying the antibiotic
- resistance most commonly mediated by enzymes that modify the antibiotic by transfer of a chemical group

  • what does this lead to?
A

Acetyltransferases
- add an acetate group

Phosphotransferases
- add a phosphate group

Nucleotidyltransferase
- add an adenine

AB can no longer bind to its target due to steric hinderance

28
Q

Modifying the antibiotic

- spread of resistance

A

Genes for AB modifying enzymes usually encoded on plasmids

-> can be shared by horizontal gene transfer

29
Q

Exporting the antibiotic

- example of an AB and how it works

A

Tetracycline

Binds to 16S rRNa
-> inhibits protein synthesis

30
Q

Exporting the antibiotic

- how does it work?

A

Resistance occurs via active transport

-> exports the drug faster than it can enter the cell

31
Q

Exporting the antibiotic

- exporting Tetracycline

A

Export occurs via drug-specific pump
= Tet pumps (TetA, TetL etc. depending on species)

Driven by proton motive force

  • > pump drug out of cell into periplasm
  • > leaves periplasm via porins
32
Q

Exporting the antibiotic

- drug exporter types

A

MDR = multi-drug resistance transporters
- not specific

5 different families

33
Q

Exporting the antibiotic

- differences between the 5 different families

A

Driven by proton motive force
OR ATP hydrolysis

Located in cytoplasmic membrane
OR spanning entire cell envelope

Often encoded on chromosome
(intrinsic resistance)

Sometimes transferred by mobile genetic elements

34
Q

3 origins + sources of AMR

A

AB are produced by microbes

Microbes naturally live in mixed communities

Bacteria need their multi-drug transporters for protection

35
Q

Origins + sources of AMR
- AB are produced by microbes
> example

A

Producer must be resistant themselves

Fungal producers = intrinsically resistant
Bacterial producers = possess immunity genes

VREs carry the vancomycin resistance van genes of the producer

36
Q

Origins + sources of AMR
- Microbes naturally live in mixed communities
> example

A

Had millions of yrs to develop resistance against ABs produced by their neighbours + competitors

e.g. B-lactamses allow bacteria to survive in presence of a penicillin producer

37
Q

Origins + sources of AMR

- Bacteria need multi drug transporters for protection

A

Protection against toxic compounds
- NOT just ABs

Need to be able to get rid of toxic metals etc.

38
Q

Spread of AMR

A

Most resistance encoded by genes

Horizontal gene transfer is v common

  • Transposons/insertion elements
  • Plasmids
  • SCCmec

Plasmids and mobile genetic elements often collect different resistance genes
= multidrug resistance

Sometimes wide-spread resistance is result of massive expansion of a single resistant clone
e.g. MRSA

39
Q

Solutions to AMR

A

Use less ABs
(e.g. vaccination to prevent infection)

Use specific ABs
(identify pathogen + selectively target that org)

Use oldest effective drug
(to lengthen the effective life span of the new ones)

Monitor treatment
(use AB long enough to clear infection, but not longer than necessary)
40
Q

Discovery of new ABs

- 2 problems

A

Science
- drug screens today keep picking up same classes of compounds

Economics

  • development of new ABs offers poor return on investment
  • long and complex approval process
  • ABs = cheap
  • short treatment times
41
Q

2 new treatment strategies

A

New ABs

Inhibitors of resistance mechanisms

42
Q

New treatment strategies
- New ABs
> example

A

Cefiderocol

Drug fuses to siderophore
-> both actively taken up into bacterium by iron uptake system
(resistant against export + bypasses intrinsic resistance)

Resistant against extended spectrum beta-lactamases (ESBLs)
(B-lactam ring is resistant)

43
Q

New treatment strategies
- Inhibitors of resistance mechanisms
> example

A

Augmentin
- treatment of some B-lactam resistant infections

Has ?????