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BMSC2210 - Chemotherapy > L17 - Resistance to chemo drugs > Flashcards

L17 - Resistance to chemo drugs Flashcards

1
Q

What is drug resistance?

A

drug no longer effective for treatment

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2
Q

3 main negative consequences of resistance to chemo drugs?

A

Increased mortality

Increased morbidity

Increased cost (new drugs, longer in hospital)

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3
Q

Is antibiotic resistance speeding up?

A

NO - mechanisms are not changing

we are just searching for it more

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4
Q

What was the concern for resistant pathogens in late 1990s?

A

gram-pos pathogens

e.g. Staph, enterococci, MRSA

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5
Q

What was the switch of concern for resistant pathogens in early 2000s?

A

agents found to treat MRSA

conern now to gram-neg pathogens

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6
Q

Why are gram-neg better defenders of drugs?

A

nature of outer membrane - efflux transporters

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7
Q

What is estimated annual death toll worldwide by 2050 for AMR resistance?

A

10mil

reduce $100tril global economic output

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8
Q

Why is resistance already found in nature?

A

due to environments pathogens are found in e.g. soil, neighbouring competitors

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9
Q

Do antibiotics CAUSE resistance?

A

No

but they are SELECTIVE AGENTS that ENRICH PRESENCE of resistant bacteria

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10
Q

2 types of acquired antibiotic resistance?

A

Endogenous (spontaneous)

Exogenous (horizontal)

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11
Q

What are mechanisms for transfer of antibiotic resistance in bacteria?

A

conjugation
transduction
transformation

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12
Q

What are genetic vehicles?

A

carry multiple diff. resistance genes

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13
Q

What can act as genetic vehicles?

A

plasmids
transposons
other mobile genetic elements e.g. SCC

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14
Q

What are the mechanisms of resistance?

A

altered target

decreased uptake

inactivation/modification

bypass

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15
Q

What is the altered target mechanism?

A

mutation/modification or increase of target

change within active site - reduced binding of drug = resistance

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16
Q

What can mediate rifampicin resistance in S. aureus?

A

alteration of RNA polymerase - mutated residues

if any of the multiple contact points to B-subunit are lost - reduction in binding

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17
Q

How does methylation of rRNA result in resistance to many drugs?

A

Cfr methlyase methylates A2503 of 23s rRNA

local perturbation of part of ribosome - reduces binding of drug

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18
Q

What was methylation of rRNA initially discovered as?

A

horizontally-acquired resistance to linezolid in S.aureus

there are MANY more drugs now experiencing resistance

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19
Q

How does vancomycin usually interact with enterococci?

A

forms H-bonds by D-ala-D-ala dipeptide

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20
Q

Vancomycin resistance in enterococci?

A

D-ala-D-lac instead - almost same as D-ala-D-ala but no H-bond formed to enterococci

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21
Q

What are the 5 genes carried in vancomycin resistant enterococci?

A

regulatory
vanR
vanS

structural
vanH
vanA
vanX

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22
Q

What do vancomycin-resistant enterococci need to do to cell wall biosynthesis?

A

new machinery to re-programme biosynthesis

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23
Q

What does vanS do?

A

detects vancomycin at cell surface

signals vanR to switch on structural genes

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24
Q

What does vanH do?

A

catalyses biosynthesis of D-lac from pyruvate pools

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25
Q

What does vanA do?

A

ligase

link D-ala to D-lac

26
Q

What dos vanX do?

A

ensure no D-ala-D-ala

if there is - it is cleaved

27
Q

What is VISA

A

vancomycin-intermediate S.aureus

28
Q

first detected strain of VISA?

A

Mu50

29
Q

What common thing do all VISA strains have?

A

significant thickening of cell wall

30
Q

What does thicker cell walls in VISA strains lead to ?

A

affinity-trapping of vancomycin

31
Q

How does affinity trapping of vancomycin work?

A

Thicker cell wall = more sites for vancomycin to bind to

more free D-ala-D-ala termini - act as decoy sites

stop penetration of the bacterium

no disruption of cell wall biosynthesis

32
Q

What happens during DECREASED UPTAKE?

A

reduced permeability (not as common)

efflux

33
Q

What can become deleted to reduce DECREASED UPTAKE?

A

porins

34
Q

Why is deleting porins for decreased uptake risky?

A

porins are essential route for nutrients

places at competitive disadvantage

35
Q

How does B-lactam resistance in P. aeruginosa involved porins?

A

downregulate OprD porin

needs other mechanisms for resistance to occur

36
Q

Are porins deleted in gram-pos?

A

No

do not see remodelling of envelope in gram-pos

37
Q

What is active efflux?

A

toxic compounds pumped from cell by efflux pump

requires proton motive force or ATP

38
Q

How can resistance arise via active efflux?

A

up-regulation of endogenous pump

horizontal acquisition of new pump

39
Q

What does the efflux transporter in gram-pos do?

A

pumped to extracellular surface

40
Q

What are the 2 efflux transporters in gram-neg?

A

1) drug pumped into periplasmic space, diffuse out of porins

2) Multiple drug efflux system, AcrAB/TolC system

41
Q

How does the AcrAB/TolC system in E.coli work? (efflux system)

A

straddles cytoplasmic and outer membrane

AcrB - transporter protein in cytoplasmic membrane - selects and translocates

TolC - substrates pass through

AcrA - adapter protein - link transporter and outer membrane channel together

42
Q

What happens during ENZYMATIC INACTIVATION or MODIFICATION?

A

Destruction
Modification

bacteria produce enzyme recognising antibiotic

43
Q

What are B-lactamases?

A

resistant to B-lactam antibiotics

44
Q

What do B-lactamases do?

A

catalyse hydrolysis of cyclic amide bonds of B-lactam ring

open ring cannot bind to target sites on PBPs

45
Q

Do gram-neg produce a lot of B-lactamases?

A

Yes - a problem

46
Q

How many classes of B-lactamases?

A

4 = A, B, C, D

47
Q

What are the 2 ‘flavours’ of B lactamases?

A

Serine

metalloenzymes

48
Q

Which are the serine B-lactamases?

A

A, C, D

49
Q

Which is the metalloenzyme?

A

B

usually zinc

50
Q

How do Serine B-lactamases work?

A

key catalytic Ser residue in active site

nucleophilic attack on B-lactam ring - opens up

similar structure to B-lactam drug target PBPs - BUT they resolve intermediate and release broken B-lactam to TURN OVER MORE MOLECULES

51
Q

Which flavour of B-lactamases can attack wider range of B-lactams?

A

Metalloenzymes

resistance to CARBAPENEMS in ADDITION to penicillins, 1st 2nd 3rd gen cephalosporins

52
Q

Why was carbapenem use increased?

A

ESBLs - could attack not only penicillins but 1st 2nd 3rd gen cephalosporins

53
Q

What are the 3 diff. families of aminoglycoside modifying enzymes?

A

ANT - adenyltransferase
AAC - acetyltransferase
APH - phosphotransferase

54
Q

How do aminoglycoside modifying enzymes work?

A

transfer bulky groups to specific points on aminoglycoside

prevents H-bond contacts with 16s rRNA

55
Q

Add what specific part of amiglycoside to the modifying enzymes add things to?

A

OH or amino group

56
Q

What happens in TARGET BYPASS

A

acquisition of alternative target

acquire alternative version of drug target insensitive to antibiotic via Horizontal GT

native protein targeted but new protein performs same function and works

(sometimes grouped with altered target)

57
Q

How does methicillin resistance in S.aureus occur?

A

MRSA - additional PBP (PBP2a)

carries out sufficient cross linking in peptidoglycan

insensitive to most B-lactams

58
Q

What is PBP2a encoded by

A

MecA

59
Q

How does methicillin work in MSSA?

A

PBPs become inactivated - no cross linking of peptidoglycan

60
Q

Can resistance mechanisms work together?

A

YES

when all mechanisms on their own aren’t sufficient, but they are TOGETHER

61
Q

Multiple mechanisms for drug resistance against B-lactams?

A

deleted porin

B-lactamase

Efflux pump

BMSC2210 - Chemotherapy (17 decks)

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