Week 7 L1 biomed application, antimicrobial resistance Flashcards

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1
Q

The definition of infectious disease

A
  • Harmful effects of one organism (‘pathogen’) on another organism (‘host’) in or on which they replicate
  • Pathogens can transfer between hosts across or (more commonly) within species
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2
Q

Penicillin use in the beginning

A
  • Penicillin, part of the larger β-lactam group, showed immediate promise, but scaling up production was a challenge
  • By 1944, Australia produced enough penicillin to allow some civilian use
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3
Q

Antimicrobial resistance evolution: why did it happen?

A
  • Individuals belonging to a given species of pathogen will vary genetically in numerous ways; this may include toxin resistance
  • Use of antimicrobials creates a selective pressure favouring survival and reproduction of the most resistant individuals
  • Over time, this will drive up the dose of an antimicrobial needed to clear an infection (minimum inhibitory concentration), or perhaps make it entirely ineffective
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4
Q

mechanism of penicillin

A
  • Penicillin mimics the structure of peptidoglycan, blocking the activity of enzymes which connect peptidoglycan molecules
  • Penicillin uptake is affected by cell wall structure - the outer membrane of Gram-negative bacteria (e.g. E. coli) mostly blocks movement, but pores within it allow access
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5
Q

Mechanism of penicillin resistance

A
  • Three main mechanisms of penicillin resistance are known
  • Target site alteration; some peptidoglycan-synthesis enzymes show much weaker binding to penicillin
  • Reduced (net) uptake; higher levels of cell membrane proteins which remove penicillin from the cell increase resistance
  • Degradation; β-lactamases break the β-lactam ring
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6
Q

The origins of penicillin resistance

A
  • Many bacteria had resistance to penicillin due to contact with Penicillum fungus
  • The spread of resistance into previously susceptible species is promoted by the capacity for bacteria to exchange genetic material, e.g. through plasmids
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7
Q

Bacterial plasmid exchange

A
  • Plasmids carrying TEM-1 β-lactamase were first identified in E. coli and Salmonella species in the mid-1960s
  • A decade later, they had also been found in Pseudomonas aeruginosa, Vibrio cholerae, Haemophilus species and Neisseria species
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8
Q

The proliferation of antimicrobials

A
  • Penicillin resistance spurred the development of alternative antimicrobials, often with naturally-occurring products as a start point
  • Major antibacterial groups include:
  • Diaminopyrimidines, quinolones (introduced in 1962) and sulfonamides (1935) - block DNA replication
  • Aminoglycosides (1946), macrolides (1952) and lincosamides (1953) - inhibit protein synthesis
  • Quinolones (1962) - block DNA unwinding and duplication
  • Tetracyclines (1948) - inhibit protein synthesis or disrupt cell wall
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9
Q

Novel antimicrobials, similar resistance
mechanisms

A
  • Sulfonamides, an antimicrobial are now rarely used, in part due to the prevalence of mutations in their target, dihydropteroate synthase
  • Aminoglycoside resistance largely occurs through enzymes which add functional groups to the antibiotics
  • Efflux pumps play an important role in quinolone resistance in some bacteria
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10
Q

The downsides of resistance to the microbe itself

A
  • Mutations affecting an antimicrobial target protein are likely to reduce its activity
  • However, plasmids can introduce an ‘alternative’ resistant form while leaving the native protein intact
  • Expressing high levels of transport proteins or enzymes which metabolise antimicrobials may cause direct harms as well as requiring energy
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11
Q

Slowing resistance development in microbes

A
  • Removing an antibiotic from use may lead to loss of resistance over time - reducing use in agriculture is a popular goal
  • Combination therapy can make formation of resistance less likely, especially where different mechanisms of resistance to each agent are favoured
  • Specific common resistance mechanisms can be directly countered, e.g. βlactamase inhibitors, efflux inhibitors
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12
Q

Antibiotic dosing

A
  • The relationship between antibiotic concentration and level of resistance is affected by many factors
  • Greater levels of antibiotic use will cause more intensive selection for resistance in commensal bacteria
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13
Q

Antibiotic persistence

A
  • In numerous populations of genetically identical bacteria, variation in lethality of a given antibiotic dose has been observed
  • Under environmental stress, a portion of bacterial cells will enter metabolic dormancy, suspending many of the processes targeted by antibiotics
  • Persistence is particularly common within biofilms
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14
Q

Alternative treatments For microbe

A
  • Antimicrobial development has slowed greatly - fewer than 50 candidate antibiotics in 2015, vs. more than 800 anti-cancer drugs
  • Alternatives - or adjuncts - to antimicrobials could be considered
  • Vaccines against several bacteria exist, with others in development
  • Bacteriophages - viruses which infect bacteria -may be particularly useful in combatting biofilms
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