Anti-Malarial Resistance Flashcards
2014 number of cases and deaths?
198 million cases
584000 deaths
Mechanism of chloroquine
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.
What types of charge can chloroquine have, and what are these dependent on?
Unprotonated/uncharged
Singly protonated
Doubly protonated
Depends on surrounding pH
What features of chloroquine make it protonatable?
Diethylamine nitrogen side-chain
Quinoline-ring heteroatom nitrogen
What is the relevance of chloroquine charge in its mode of action?
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.
By how much have malaria mortality rates dropped?
Since 2000:
Globally 47%
Africa 54%
What is the genetic determinant in chloroquine resistance?
Polymorphisms in pfcrt (P.falciparum chloroquine resistance transporter)
What mutation is found in all chloroquine resistant parasites?
K76T
What is the charged drug leak model?
pfcrt facilitates movement of doubly protonated protonated chloroquine down its concentration gradient out of the food vacuole.
How does K76T function?
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.
How has pfcrt allele reduced in Malawi?
Replacement of chloroquine first line to sulfadoxine pyrimethamine
Why has there been a switch to sulfadoxine pyrimethamine as a first line drug for Rx uncomplicated malaria?
Growing resistance to chloroquine in many countries.
Where can resistance to sulfadoxine pyrimethamine be found?
Southeast Asia, South America, Africa
Where and on what do anti folates act?
Folate pathway in pyrimidine and methionine productions. Two drugs work in tandem on DHPS and DHFR enzymes.
How does resistance come about in antifolates?
Point mutation in DHFR enzyme, leading to reduced drug binding
What mutations cause antifolate resistance?
C59R, S108N, N51I, I164L
Which mutations cause sulfadoxine pyrimethamine to fail?
C59R, S108N, N51I
What mutations cause LapDap to fail?
C59R, S108N, N51I, I164L
Why was LapDap withdrawn from Africa in 2008?
Causes anaemia in those with G6PD deficiency
What is attributed to artemisinin resistance, especially in Southeast Asia?
Delayed parasite clearance giving rise to concern about the therapeutic life-span of first generation artemisinin
Mechanism of artemisinin.
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.
Molecular marker for artemisinin resistance.
K13-propeller mutation.
What four mutations in K13-propeller are associated with increased parasite clearance half-lives?
Y493H, R539T, I543T, C580Y
What is the theory of C580Y mutation in K13-propeller influence on resistance?
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).
What is the basis of new drugs in production?
Artemisinin based
