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BIOL334 > BIOL334- Antibiotic Resistance > Flashcards

BIOL334- Antibiotic Resistance Flashcards

1
Q

Delivery of antibiotics

A
  • Humans- tablets/ IV antibiotics (drip)/ injection
  • Animal husbandry- breeding animals in close proximity. Antibiotics help yield and protect from infection.
  • Back to humans again (meat, chicken, fish, chemicals in environment)
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2
Q

What is an antibiotic?

A
  • A substance produced or derived from certain fungi, bacteria and other organisms that can destroy or inhibit the growth of other microorganisms.
  • Prevention and treatment of infectious diseases
  • Extremely diverse group of products called secondary metabolites
  • Not essential for cell growth or reproduction
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3
Q

How did antibiotics evolve?

A
  • If you can establish a habitat you kill off the neighbours by antibiotics you reduce competition
  • We now exploit them
  • There is a metabolic burden of producing them so must be beneficial
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4
Q

Sources of antibiotics

A
  • Streptomyces common genus (bacteria) which produce a whole range of antibiotics
  • Penicullum genus (fungi)
  • E.g., vancomycin, last line antibiotic
  • Steptomycin
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5
Q

Describe the mechanism of Beta lactam antibiotics

A
  • Inhibit cell wall synthesis
  • A bacterial cell wall is composed of peptidoglycan composed of NAG-NAM changes that are cross linked by peptide bridges between the subunits
  • Penicillin interfere with the linking enzymes and NAM subunits remain unattached to their neighbours
  • The cell continues to grow regardless, and eventually burst from osmotic pressure because integrity of peptidoglycan not maintained
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6
Q

Give examples of Beta lactam antibiotics

A

Penicillin
Cephalosporins
Vancomycin

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7
Q

Resistance to beta lactam antibiotics- mechanism

A

Beta lactamases: degrades beta lactam ring and inactivates the antibiotics

  • By passes antibiotic resistance by providing an alternative route to resistance
  • The antibiotic is interrupted by a B lactamase enzyme in the periplasmic space and this destroys the action of the antibiotic
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8
Q

What are Carbapenamases?

A
  • Type of beta lactam antibiotic
  • Used as last line antibiotics when others are resistant
  • Fairly new beta lactam antibiotic
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9
Q

Describe how antibiotics prevent bacterial growth via targeting protein synthesis

A
  • Tetracycline, Streptomycin

- All target the ribosome to affect protein synthesis.

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10
Q

Describe how Streptomycin prevents bacterial growth

A
  • Binds to 30S part of the ribosome causing a conformational change and protein synthesis is inhibited
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11
Q

Describe how tetracycline inhibits bacterial growth

A
  • Tetracycline prevents docking of tRNAs to the messenger- stops protein synthesis
  • Preventing the attachment of aminoacyl-tRNA to the ribosomal acceptor (A) site.
  • Tetracycline resistance is often due to the acquisition of new genes, which code for energy-dependent efflux of tetracyclines or for a protein that protects bacterial ribosomes from the action of tetracyclines
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12
Q

What was the first tetracycline resistant bacterium? And when was it discovered

A

The first tetracycline-resistant bacterium, Shigella dysenteriae, was isolated in 1953

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13
Q

Describe the mode of action of antibiotics that disrupt metabolic pathways

A
  • We don’t want these antibiotics to affect eukaryotic cells
  • They only target prokaryotic cells
  • Examples is Sulfonamides
  • PABA (an intermediate) needed for folic acid synthesis in bacteria and protozoa.
  • Some sulfaonamides competitively inhibits enzymatic reactions involving PABA.
  • Others act as analogues of the enzyme
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14
Q

What are broad spectrum antibiotics (example)

A
  • Any antibiotic that acts against a wide range of disease-causing bacteria.
  • Example is Streptomycin targets gram positive and negative and Chlamydias
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15
Q

What are narrow spectrum antibiotics (example)

A
  • An antibiotic that is only able to kill or inhibit limited species of bacteria
  • Example is Ribavirin that only effects viruses
  • Polymyxin- only affected gram negatives
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16
Q

Prescription of antibiotics data (2007)

A
  • 35 million prescriptions in 2007

- Aim to reduce by 25% by 2024

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17
Q

Describe how you can show the development of antibiotic resistance in a lab

A
  • Culture cells
  • Apply the drug
  • Most will be killed but some will persist (mutations arise that cause resistance)
  • So the pathogen grows
  • Can use 2/3 antibiotics in hospitals to eradicate infections
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18
Q

Causes of Antimicrobial Drug Resistance

A
  • Incorrect prescribing practices
  • Overuse
  • Non- adherence by patients (not taking the full course)
  • Counterfeit drugs
  • Use of antibiotics in animal husbandry and agriculture
  • Community acquired drug resistance e.g., TB hospital acquired resistance- pathogens contracted in hospitals contain resistance
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19
Q

Causes of Antimicrobial Drug Resistance

A
  • Incorrect prescribing practices
  • Overuse
  • Non- adherence by patients (not taking the full course)
  • Counterfeit drugs
  • Use of antibiotics in animal husbandry and agriculture
  • Community acquired drug resistance e.g., TB hospital acquired resistance- pathogens contracted in hospitals contain resistance
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20
Q

Consequences of antimicrobial drug resistance

A
  • Prolonged hospital admissions-pressure on healthcare systems
  • Higher death rates from infection
  • Requires more expensive toxic drugs
  • Higher health care costs TB costs 3000 to treat but 30,000 when it is a resistant strain
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21
Q

Why is the spread of antibiotics in the environment complex?

A

Spread is via water, food, industry, crops, food, animal farming, abattoirs, hospitals, farm effluent and humans

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22
Q

What is the resistome?

A

The resistome is a collection of all the antibiotic resistance genes and their precursors in both pathogenic and non-pathogenic bacteria.

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23
Q

Global antibiotic resistance reservoirs

A

Soil
Freshwater
Oceans
Global resistome

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24
Q

What is passive resistance

A

Antibiotic has no target or cannot enter the cell

25
Q

What is ‘mutation’ resistance

A

Target site of antibiotic changes so antibiotic is ineffective

26
Q

What is acquired resistance

A

Actively acquired resistance occurs via genetic elements e.g., plasmids

  • When a particular microorganism obtains the ability to resist the activity of a particular antimicrobial agent to which it was previously susceptible.
  • Acquisition of genes from other microorganisms via transformation, transduction or conjugation
  • Often plasmid encoded aided by transposons and integrons
27
Q

Give an example of mutation resistance to antibiotics

A
  • Steptomycin binds to the 16S rRNA of the 30S subunit of the bacterial ribosome
  • Causes inhibition of protein synthesis
  • Mutation in 16S rRNA gene by point mutation (inversion, insertion, deletion or duplication) changes the active site and therefore streptomycin is no longer effective
28
Q

Describe transformation

A
  • Free DNA in the environment in taken up by a competent recipient
  • The donor can be live or dead
  • The recipient must be living
29
Q

Describe transduction

A
  • Process by which a virus transfers genetic material from one bacterium to another e.g., by bacteriophage
  • Recipient must be living
30
Q

Describe conjugation

A
  • Cell to cell contact by two bacteria
  • During conjugation, one bacterium serves as the donor of the genetic material, and the other serves as the recipient. The donor bacterium carries a DNA sequence called the fertility factor, or F-factor.
  • Involves formation of sex pilus
31
Q

What are conjugative plasmids

A
  • Extra-chromosomal DNA elements that are capable of horizontal transmission and are found in many natural isolated bacteria. Can carry multiple functions
32
Q

What are insertion sequences

A
  • Small bits of DNA that jump around these are hotspots for recombination
  • IS’s are small transposable elements, commonly found in bacterial genomes.
  • Transposable elements have inverted repeats and carry resistance genes between the IR
33
Q

What are integrons

A

DNA which sit in the chromosome or plasmid and are hotspots to receive new genes
- genetic elements that allow efficient capture and expression of exogenous genes.

34
Q

What is collective resistance

A
  • Resistant bacterium and a non resistant bacterium
  • As they grow the resistant bacterium uses up the antibiotic and you get growth of the non resistant bacteria in that area too. (hides in the space of resistant organism)
35
Q

3 types of point mutation in AR

A

Positive: Beneficial to bacterium
Neutral: No effect
Negative: Bacterium dies

36
Q

What is MRSA

A

Methicillin-resistant Staphylococcus aureus, a type of bacteria that is resistant to beta lactamases (pencillins, cephalosporins)
- Opportunistic pathogen

37
Q

When was methicillin introduced?

How long after did MRSA appear?

A

1956
1961- MRSA discovered in England
(5 years later)
1968: MRSA US

38
Q

by 1974 what % of Staphylococcus aureus infections were MRSA

A

2%

39
Q

In what way are community acquired MRSA and hospital acquired MRSA different?

A

genetically different

40
Q

How many deaths per year does MRSA cause in the US

A

~19,000

41
Q

Which new antibiotic is now used to treated MRSA

A

Vancomycin- last line antibiotic

But some resistance to vancomycin already observed in hopsitals

42
Q

Describe the trend in MRSA infections in the UK

Why is this?

A
  • Dropped between 2000-2011
  • Now fairly steady
  • this is due to implication of screening patients, keeping patients separate, doctors not wearing lab coats and washing hands- implemented in 2006 (national protection measures)
  • Decreasing mortality from MRSA
43
Q

Describe why MRSA is considered a global problem

A
  • Spain and Italy are hotspots

- UK on red alert (very high MRSA) in 2000-2005, now orange

44
Q

MRSA virulence

A

SSC mec (staphylococcal cassette chromosome mec)

  • a mobile genetic element which includes the mecA gene
  • mecA encodes resistance to antibiotic methicillin
  • MecA encodes PBP2A (penicillin binding protein 2a)
  • PBP2A has a low affinity for beta lactam antibiotics
  • This enables transpeptidase activity in the presence of B lactams
  • Preventing them from inhibiting cell wall synthesis
  • New variants of MecA 1-4

Arginine catabolic mobile element

  • A virulence factor present in many MRSA strains but not MSSA (community acquired)
  • ACME facilitates stable skin colonisation and wound infection and person to person transmission
45
Q

What is the SSC mec

A

Staphylococcal cassette chromosome mec

- A mobile genetic element which induces the mecA gene

46
Q

What is the MecA gene

A
  • Encodes penicillin binding protein 2 a (PBP2a)

- PBP2a has a low affinity for B lactam antibiotics such as methicillin

47
Q

What is the PBP2a

A

Penicillin binding protein 2a

  • encoded by MecA gene
  • PBP2A has a low affinity for beta lactam antibiotics
  • This enables transpeptidase activity in the presence of B lactam antibiotics
  • Can inhibit the antibiotic mechanism (that is inhibiting cell wall synthesis)
  • PBP2a is an alternative protein enzyme that zips cell wall polymers together- low affinity to B lactase so able to produce a different PBP that bypasses the antibiotic
48
Q

What is ACME

A

Arginine catabolic mobile element

  • A virulence factor present in many MRSA strains but not MSSA (community acquired)
  • Facilitates stable skin colonisation, person to person transmission and wound infection
49
Q

Origin of MRSA

A
  • Researchers believe AR evolved in Staph aureus as an adaptation to having to exist side by side on the skin of hedgehogs with the fungus Trichophyton which produces its own antibiotics
50
Q

What is NDM1

A
  • New Delhi carbapenemase

- NDM-1 is a carbapenemase B lactamase- an enzyme that hydrolyses and inactivates a broad range of B lactam antibiotics

51
Q

Where was NDM-1 first detected

A
  • Klebsiella pneumonia from a Sweedish patient
52
Q

In which bacteria is NDM-1 commonly found?

A

Gram negatives

E.coli and Klebsiella pneumoniae

53
Q

How does the NDM-1 gene spread

A

Horizontal gene transfer

54
Q

Colistin resistance NDM-1

A

Colistin- last line antibiotic

  • NDM-1 found to be resistant to this now
  • Escaped from Chinese pig farming- into environment
55
Q

How can we manage AR (2 ways)

A
  • Managing existing resistance pathogens

- Avoiding future evolution of resistance

56
Q

Give an example of ‘Managing existing antibiotic resistance pathogens’

A

MRSA

  • improving hygeine
  • screening visitors
  • isolating patients
57
Q

How can we avoid evolution of AR?

A
  • Changing selection on bacteria
  • Reduce inappropriate prescription of antibiotics (colds)
  • Increase public awareness and educate doctors
  • Reduce agricultural use of antibiotics
  • Combat the scrounge of low quality counterfeit antibiotics (LICs in particular)
  • increase number of patients who finish their course of antibiotics
  • Make antibiotics more affordable to low income regions
  • Restrict use of new last line antibiotics
  • Use other treatments where possible- phages (open wounds), vaccines
  • Get pharmaceutical companies to make new antibiotics (last one found in 80s)
58
Q

Why should you take the full course of antibiotics?

A
  • When you have a bacterial infection that is antibiotic sensitive within the first few hours-days of taking antibiotics there is a rapid reduction in the number of bacteria causing it
  • So symptoms improve (inflammation at the site of infection reduces)
  • But there remains a small population of bacteria that we refer to as persisters
  • If you stop taking antibiotics when you feel better the persisters can grow back and cause a reinfection
  • The bacteria that cause this recurrent infection have experienced a sub-lethal exposure to first antibiotic
  • But it is possible they survived because they were hiding from the antibiotic
  • Or genetically better at dealing with the antibiotic (If this is the case they may be resistant to the antibiotic).
  • But it is important to take them all in case the persisters were hiding- the full course would kill them
59
Q

Example of phage used for bacterial infection (alternative to antibiotics)

A

Phages have been reported to be effective in treating staphylococcal lung infections, P. aeruginosa infections in cystic fibrosis patients, eye infections, , neonatal sepsis, urinary tract infections, and surgical wound infections

BIOL334 (9 decks)

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