Anti-Malarial Resistance

Question 1

2014 number of cases and deaths?

Answer 1

198 million cases

584000 deaths

Question 2

Mechanism of chloroquine

Answer 2

Binds to haem (by-product of haemoglobin degradation) in parasite digestive food vacuole. This prevents crystallisation of haem to non-toxic haemozoin.
Harm causes membrane damage and parasite death.

Question 3

What types of charge can chloroquine have, and what are these dependent on?

Answer 3

Unprotonated/uncharged
Singly protonated
Doubly protonated

Depends on surrounding pH

Question 4

What features of chloroquine make it protonatable?

Answer 4

Diethylamine nitrogen side-chain

Quinoline-ring heteroatom nitrogen

Question 5

What is the relevance of chloroquine charge in its mode of action?

Answer 5

The higher the charge the more impermeable chloroquine is to membranes. If pH is ~5.5 it’s doubly protonated.
‘Proton-trapping’ results in drug accumulation several thousand fold in the food vacuole.

Question 6

By how much have malaria mortality rates dropped?

Answer 6

Since 2000:

Globally 47%
Africa 54%

Question 7

What is the genetic determinant in chloroquine resistance?

Answer 7

Polymorphisms in pfcrt (P.falciparum chloroquine resistance transporter)

Question 8

What mutation is found in all chloroquine resistant parasites?

Answer 8

K76T

Question 9

What is the charged drug leak model?

Answer 9

pfcrt facilitates movement of doubly protonated protonated chloroquine down its concentration gradient out of the food vacuole.

Question 10

How does K76T function?

Answer 10

By replacing lysine (K) with threonine (T). Lysine is positively charged reselling chloroquine, threonine has no charge allowing chloroquine to diffuse into parasite cytoplasm. This is added by chloroquine concentration gradient and proton gradient across the food vacuole membrane.

Question 11

How has pfcrt allele reduced in Malawi?

Answer 11

Replacement of chloroquine first line to sulfadoxine pyrimethamine

Question 12

Why has there been a switch to sulfadoxine pyrimethamine as a first line drug for Rx uncomplicated malaria?

Answer 12

Growing resistance to chloroquine in many countries.

Question 13

Where can resistance to sulfadoxine pyrimethamine be found?

Answer 13

Southeast Asia, South America, Africa

Question 14

Where and on what do anti folates act?

Answer 14

Folate pathway in pyrimidine and methionine productions. Two drugs work in tandem on DHPS and DHFR enzymes.

Question 15

How does resistance come about in antifolates?

Answer 15

Point mutation in DHFR enzyme, leading to reduced drug binding

Question 16

What mutations cause antifolate resistance?

Answer 16

C59R, S108N, N51I, I164L

Question 17

Which mutations cause sulfadoxine pyrimethamine to fail?

Answer 17

C59R, S108N, N51I

Question 18

What mutations cause LapDap to fail?

Answer 18

C59R, S108N, N51I, I164L

Question 19

Why was LapDap withdrawn from Africa in 2008?

Answer 19

Causes anaemia in those with G6PD deficiency

Question 20

What is attributed to artemisinin resistance, especially in Southeast Asia?

Answer 20

Delayed parasite clearance giving rise to concern about the therapeutic life-span of first generation artemisinin

Question 21

Mechanism of artemisinin.

Answer 21

Artemisinin’s are endoperoxides (containing peroxide bridge). Their cleavage generates short lived cytotoxic oxyradicals in the presence of haem iron or free iron Fe2+.
Activated endoperoxides antimalarials disrupt parasite functions and enzymes - haem detoxification pathway and parasite mitochondrion.

Question 22

Molecular marker for artemisinin resistance.

Answer 22

K13-propeller mutation.

Question 23

What four mutations in K13-propeller are associated with increased parasite clearance half-lives?

Answer 23

Y493H, R539T, I543T, C580Y

Question 24

What is the theory of C580Y mutation in K13-propeller influence on resistance?

Answer 24

C580Y reduces polyubiquitonation of parasite kinase PfPI3K. This results in increased kinase levels and its product PI3P (which may influence one or more antioxidant defence/repair mechanisms).

Question 25

What is the basis of new drugs in production?

Answer 25

Artemisinin based