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2021-22 Clinical microbiology > Antibiotics and Antimicrobial Resistance > Flashcards

Antibiotics and Antimicrobial Resistance Flashcards

1
Q

What is antibiotic resistance?

A
  • The ability of bacteria to survive treatment by certain antibiotics.
  • Bacteria which are resistant to multiple antibiotics are called multi-drug resistant
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2
Q

Why is the problem of AMR so bad?

A

Antibiotic use in humans

  • People not taking complete courses of antibiotics
  • Inappropriate prescriptions or over-prescription of antibiotics
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3
Q

Why is the problem of AMR so bad: Non-therapeutic uses of antibiotics

A

•To treat sick animals•As growth promoters in

agriculture (Not in the EU!)

  • Biocide use (to extend shelf life)
  • Brewing
  • Veterinary medicine
  • Aquaculture
  • Anti-fouling (industrial, ships)
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4
Q

Problem of AMR: No new antibiotics!

A

Golden age of antibiotic discovery was from 1930-1970!

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5
Q

Why do antibiotics stop working?

A

What doesn’t kill them makes them makes them stronger!

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6
Q

How do bacteria become resistant to antibiotics?

A
  1. Make enzymes which alter or destroy the antibiotic
  2. Alteration of target site
  3. Prevent antibiotics getting into the cell
  4. Pump (efflux) the antibiotic out of the cell
  5. Temporarily change their metabolism (dormancy)
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7
Q

Show how bacteria become resistant to antibiotics?

A
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8
Q

Enzymes which alter or destroy the antibiotic

A
  • The β-lactamases (penicillinases)
  • Adaptive resistance
  • Hydrolyse the β-lactam ring
  • Broad spectrum resistance mechanism
  • Gram –ve β-lactamases excreted
  • Some classes can be inhibited by Clavulanic acid (used in combination with β-lactam antibiotic)
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9
Q

Give examples of organisms with enzymes which alter or destroy antibiotics

A
  • Extended spectrum β-lactamases (ESBLs)Discovered in 1980sPlasmid-encoded (HGT)Confer multi-resistance
  • Inhibit a wide range of β-lactams

Resistance to penicillins but not extended-spectrum cephalosporins

Carbapenems used (resistance reported)

  • Derive from genes for TEM-1, TEM-2 or

SHV-1 by mutations in in the active site

  • TEM ESBL: 90% E. coli resistance. Also H. influenzae, K. pneumoniae, N. gonorrhoeae
  • SHV ESBL: K. pneumoniae
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10
Q

Pump (efflux) the antibiotic out of the cell

A
  • Energy dependent (active) transport of unwanted substances out of the bacterial cell
  • Adaptive resistance
  • Located in cytoplasmic membrane
  • Primary active transporters are powered by ATP hydrolysis
  • Secondary active transporters pump(H+)

Uniporters, symporters, antiporters

  • 5 Superfamilies:
  1. Major facilitator superfamily (MFS)
  2. ATP-binding cassette superfamily (ABC)
  3. Small multidrug resistance superfamily (SMR)
  4. Resistance-nodulation-cell division superfamily (RND)
  5. Multi-antimicrobial extrusion protein (MATE)
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11
Q

Did efflux pumps evolve to provide resistance to antibiotics?

A
  • Didn’t evolve for antibiotics
  • Lipids (pH homeostasis), environmental toxins etc.
  • Bacteria pump antibiotics out of the cell using efflux pumps
  • Antibiotics present selective pressure for bacteria with these efflux pumps
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12
Q

Explain Efflux pumps

A
  • Chromosomal or on plasmids (HGT)
  • Intrinsic and acquired (from HGT) resistance
  • Expression of several classes of efflux pump can lead to a broad spectrum of resistance
  • Efflux pump inhibitors exist Verapamil/PABN/CCCP
  • Mostly function by disrupting H+ motive force – very toxic, no clinical application
  • Triclosan – antibacterial and antifungal agent
  • Toothpaste, soaps, detergents etc.
  • Triclosan elect for broad spectrum efflux pump expressing bacteria (resistant to Triclosan)
  • Banned by FDA in 2017
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13
Q

Alteration of the target site

A
  • EXAMPLE: DNA Gyrase and Fluoroquinolone resistance
  • DNA Gyrase – DNA synthesis
  • Fluoroquinolones block DNA-gyrase-DNA complex formation
  • Resistance by chromosomal mutations in both genes
  • More common – mutations in GyrA (A subunit of DNA Gyrase)
  • Prevent fluoroquinolone binding
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14
Q

Temporarily change their metabolism

A
  • Escape effect of antibiotic without undergoing genetic change
  • “Persister” cell formation (because they are persistent)
  • Adaptive resistance
  • Do not grow in the presence of antibiotic but are tolerant to its presence
  • Small fraction of population >1%
  • Mechanism not well understood
  • Changes to metabolism made possible by metabolomics
  • Not really “dormant” although sometimes described as such
  • Phenotypic variance
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15
Q

Give examples of bacteria that temporarily change their metabolism

A
  • EXAMPLE: Non-replicating persistence (NRP) in Mycobacterium tuberculosis
  • Causes LTBI
  • Non-replicating, metabolically active, multi-drug tolerant
  • Induced by <pO2 and nutrient starvation
  • Can persist for many years
  • TB treatment regimen is inactive (isoniazid and rifampicin have acute effect upon re-activation)
  • Killed by metronidazole and Pretomanid (PA-824) under NRP
  • Limited uptake in granuloma
  • We need more NRP-active drugs
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15
Q

What does alteration of the target site involve?

A
  • Selection of spontaneous mutations in the gene encoding the drug target
  • Changes the amino acid sequence at site of action
  • Mutational Resistance
  • Reduced affinity of target for drug
  • Antibiotic no longer functions
  • Examples:
  • RNA polymerase (Rifamycin)
  • DNA gyrase (Quinolones)
  • Have been found for EVERY class of antibiotic
17
Q

Prevent antibiotics getting in to the cell

A
  • Antibiotics require access to bacterial cell machinery to be effective
  • Reduce OM permeability
  • Adaptive resistance
  • Porin channels allow antibiotics to cross Gram –ve outer membrane
  • Modifying cell membrane porin channels
  • Frequency
  • Size
  • Selectivity
  • Example: aminoglycoside resistance
18
Q

Prevent antibiotics getting in to the cell: Explain this mechanism

Which bacteria can this be observed in?

A
  • Increase the Outer Membrane Permeability
  • Hydrophobic drugs diffuse across lipid bilayer
  • Eg. Macrolides
  • Increase saturated lipid composition of OM reduces permeability
  • Hydrophilic drugs use porins for accessing cell
  • Eg. β-lactams, tetracycline, fluoroquinolones
  • Down-regulation, loss or functional change of OmpF and OmpC (Outer membrane porin F/C) leads to antibiotic resistance
  • Observed in E. coli, P. aeruginosa, N. gonorrhoeae, Enterobacter aerogenes and K. pneumoniae
19
Q

The future of antibiotic resistance

A

By 2050 AMR will be the leading cause of death

20
Q

Meeting the need

A

Scientists:

•Research into new drugs and new drug targets

Doctors:

•Reducing prescriptions where possible and prescribing the right antibiotics

Non-Government Organisations:

•e.g. antibiotic action are raising awareness of the issue and trying to find solutions

Government:

•The PM has set up a panel, headed by an economist, to investigate why no new drugs are being made and to find economic solutions

2021-22 Clinical microbiology (10 decks)

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