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MODA Questions > Drug Resistance > Flashcards

Drug Resistance Flashcards

1
Q

What may confer intrinsic resistance to an organism?

A
  1. Lack of expression for a receptor
  2. Inadequate drug concentration
  3. Inability of drug to access target in organism
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2
Q

Why is rifampin not effective against fungi?

A

Does inhibit fungal DNA-dependent DNA polymerase however cannot pass through fungal cell envelope to site of action

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3
Q

What does M. tuberculosis have in its cell wall?

A

Mycolic acids, making it waxy and impermeable

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4
Q

What are the main mechanisms of drug resistance?

A
  1. Enzymatic inactivation of drug
  2. Replacement, modification or amplification of drug target
  3. Decreased drug uptake/increased drug efflux
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5
Q

How do β-lactamases work?

A

Hydrolyse strained β-lactam ring of β-lactam antibiotic

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6
Q

How does the β-lactam ring exert its antibiotic effect?

A

Chemically reactive acylating group modifies serine residue in active site of peptidoglycan transpeptidases

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7
Q

How effective is β-lactamase?

A

One E. coli cell can secrete 100,000 enzymes

Each enzyme can hydrolyse 1000 β-lactams per second

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8
Q

What are the A, C and D β-lactamases?

A

Active site serine enzymes

Architectural and mechanical similarities to PG transpeptidases

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9
Q

What is the outcome of the reaction catalysed by PG transpeptidases?

A

Suicide

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10
Q

What is the outcome of A, B and D β-lactamases?

A

Turnover

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11
Q

What is the lifetime of the penicilloyl-transpeptidase acyl enzyme reaction?

A

Extremely slow

Half-life for deacylation is 90 mins

Due to exclusion of water from active site

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12
Q

What does lactamase activity involve?

A

Hydrolysis instead of capture of acyl-O-Ser enzyme by an amine

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13
Q

How do class B β-lactamases work?

A

Zinc-dependent

Use zinc to activate a water molecule and catalyse its direct addition to the β-lactam ring

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14
Q

What can extended spectrum β-lactamases (ESBL) hydrolyse?

A

Oxyimino-cephalosporins

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15
Q

How did CTX-M arise?

A

Plasmid transfer from pre-existing chromosomal ESBL genes from Kluyvera species

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16
Q

How do bacteria develop resistance to aminoglycosides?

A

Covalent modification of specificity-conferring OH and NH2 groups, interfering with recognition by 30S rRNA

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17
Q

What are the three types of modification to aminoglycosides by resistant bacteria?

A
  1. N-acetylation of NH2 by acetyl-CoA
  2. O-phosphoryl transfer of γ-phosphate group from ATP to OH moiety
  3. O-adenylyl transfer α-phosphate of ATP, resulting in transfer to OH moiety
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18
Q

How does methicillin deactivate β-lactamases?

A

Bulky side chain substituent enhanced lifetime of covalent penicilloyl-O-lactamase acyl enzyme intermediate against hydrolysis

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19
Q

How is MRSA resistant to methicillin?

A

Has acquired the mecA gene

Encodes new β-lactam-insensitive bifunctional transglycosylase/transpeptidase protein (PBP2A)

20
Q

Which auxiliary genes are expressed in MRSA?

A

Fem (factor essential for methicillin resistance)

Confers high level of β-lactam resistance when expressed alongside the MecA gene

21
Q

What does the fem gene do?

A

Adds a penta-glycyl cross-bridge to PG chains before cross-linking

Modified strand is better substrate for MecA transpeptidase

22
Q

What is the leading cause of endocarditis?

A

Enterococci

23
Q

What do VanS and VanR form?

A

Two component signal transduction pathway for inducible reprogramming to vancomycin resistance

Sensor and response regulator

24
Q

What is the effect of VanH, VanA and VanX enzymes?

A

Reprogramming of PG terminus from N-acyl-D-ala-D-ala to N-acyl-D-ala-D-lactate

25
Q

How is vancomycin sensed in the environment?

A

VanS receptor kinase

26
Q

What does VanS do once it senses vancomycin?

A

Phosphorylates and activates VanR

27
Q

What does VanR do?

A
  1. Further enhances expression of VanS/VanR operon

2. Switches on expression of VanH/VanA/VanX operon

28
Q

What is the major route of resistance to macrolides?

A

Methylation of adenine A2058 in 23S rRNA of 50S ribosome subunit as this is close to the macrolide-binding site

29
Q

What type of drugs is reduced drug influx more effective for?

A

Hydrophilic drugs

30
Q

How are aminoglycosides taken up in P. aeruginosa?

A

Porins in outer membrane

31
Q

How does aminoglycoside resistance arise?

A
  1. Decreased expression of porins in outer membrane
  2. Modifications to LPS outer leaflet
  3. Decreased expression of oligopeptide transporters
32
Q

How are aminoglycosides taken up into the cytoplasm from the periplasm?

A

Oligopeptide transporters

33
Q

What type of drugs is increased drug efflux more effective for?

A

Hydrophobic drugs

34
Q

What type of drug-transporters are more common in prokaryotes?

A

Secondary-active drug transporters

Use inward movement of sodium ions or protons

35
Q

What are secondary-active drug transporters associated with in gram-negative bacteria?

A
  1. Accessory protein spanning the periplasm

2. Outer membrane porin to allow drug transport across outer leaflet into external environment

36
Q

What is multiple drug resistance?

A

Simultaneous expression of multiple antibiotic resistance mechanisms, each specific for a drug or class of drug

37
Q

What is a regulon?

A

Gene master switch

Enables co-expression of genes localised at different positions on genome

38
Q

What is multi-drug resistance?

A

Drug efflux pump confers resistance to a wide variety of drugs due to broad specificity of pump

39
Q

What causes azole resistance?

A
  1. Alterations in activity and amount of enzymes involved in ergosterol synthesis
  2. Active azole efflux
40
Q

How do herpesviruses become resistant to purine analogues?

A

Change in substrate-specificity of viral purine-activating enzyme thymidine kinase disables phosphorylation of analogue so it is not activated

41
Q

How does HIV develop resistance to reverse transcriptase inhibitors or protease inhibitors?

A

Mutations in enzymes that prevent interaction between enzyme and inhibitor

42
Q

How do parasites become resistant to chloroquine?

A

Accumulate chloroquine in their food vacuoles much less efficiently so drug excluded from site of action

Due to chloroquine resistance transporter

43
Q

How are cancer drugs enzymatically inactivated?

A
  1. Cytochrome P450 systems

2. Conjugation by glutathione-S-transferase

44
Q

How do cancer cells become resistant to topo poisons?

A

Possess modified topoisomerases

45
Q

How do cancer cells become resistant to nitrosureas?

A

High levels of alkyltransferases which repair guanine lesions, preventing DNA cross-linking

46
Q

What causes methotrexate resistance?

A
  1. Enhanced expression of dihydrofolate reductase

2. Reduced uptake due to mutations in folate carrier

MODA Questions (7 decks)

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