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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
How is vancomycin sensed in the environment?
VanS receptor kinase
26
What does VanS do once it senses vancomycin?
Phosphorylates and activates VanR
27
What does VanR do?
1. Further enhances expression of VanS/VanR operon | 2. Switches on expression of VanH/VanA/VanX operon
28
What is the major route of resistance to macrolides?
Methylation of adenine A2058 in 23S rRNA of 50S ribosome subunit as this is close to the macrolide-binding site
29
What type of drugs is reduced drug influx more effective for?
Hydrophilic drugs
30
How are aminoglycosides taken up in P. aeruginosa?
Porins in outer membrane
31
How does aminoglycoside resistance arise?
1. Decreased expression of porins in outer membrane 2. Modifications to LPS outer leaflet 3. Decreased expression of oligopeptide transporters
32
How are aminoglycosides taken up into the cytoplasm from the periplasm?
Oligopeptide transporters
33
What type of drugs is increased drug efflux more effective for?
Hydrophobic drugs
34
What type of drug-transporters are more common in prokaryotes?
Secondary-active drug transporters Use inward movement of sodium ions or protons
35
What are secondary-active drug transporters associated with in gram-negative bacteria?
1. Accessory protein spanning the periplasm | 2. Outer membrane porin to allow drug transport across outer leaflet into external environment
36
What is multiple drug resistance?
Simultaneous expression of multiple antibiotic resistance mechanisms, each specific for a drug or class of drug
37
What is a regulon?
Gene master switch Enables co-expression of genes localised at different positions on genome
38
What is multi-drug resistance?
Drug efflux pump confers resistance to a wide variety of drugs due to broad specificity of pump
39
What causes azole resistance?
1. Alterations in activity and amount of enzymes involved in ergosterol synthesis 2. Active azole efflux
40
How do herpesviruses become resistant to purine analogues?
Change in substrate-specificity of viral purine-activating enzyme thymidine kinase disables phosphorylation of analogue so it is not activated
41
How does HIV develop resistance to reverse transcriptase inhibitors or protease inhibitors?
Mutations in enzymes that prevent interaction between enzyme and inhibitor
42
How do parasites become resistant to chloroquine?
Accumulate chloroquine in their food vacuoles much less efficiently so drug excluded from site of action Due to chloroquine resistance transporter
43
How are cancer drugs enzymatically inactivated?
1. Cytochrome P450 systems | 2. Conjugation by glutathione-S-transferase
44
How do cancer cells become resistant to topo poisons?
Possess modified topoisomerases
45
How do cancer cells become resistant to nitrosureas?
High levels of alkyltransferases which repair guanine lesions, preventing DNA cross-linking
46
What causes methotrexate resistance?
1. Enhanced expression of dihydrofolate reductase | 2. Reduced uptake due to mutations in folate carrier

MODA Questions (7 decks)

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