this presentation deals with the drugs for choice for malaria, their mode of action, resistance development and its distribution, how to evaluate resistance development and reasons for developing resistance.

1. Molecular
markers for the
detection of
malaria drug
resistance
Presented by-
Anil kumar
M.Sc PHE Ist year
VCRC(ICMR)

2. NEED…???
• As per 2015, 214 million new cases reported for
malaria worldwide(African region-88%, South East
Asian region-10% and East Mediterranean region-
2% ).
• About 438,000 deaths worldwide.
• 3.2 billion people (about half of the population of
world) live in high risk zone of malaria.
• About 12 billon USD per year expenses on malaria
(illness, treatment and diagnosis) globally.
• In 2014 itself 535 death in India.
• Drug resistance increases the burden of disease,
mortality and financial expenses.

3. INTRODUCTION
• Malaria is caused by mosquito vector.
• Parasites involved are - P. falciparum, P. malariae, P.
vivax and P. ovale.
• Different drugs are known for different mechanism of
action.
• Ability of a parasite strain to survive and/or to multiply
despite the administration and absorption of a drug
given in doses equal or higher than those usually
recommended, but within the limits of tolerance of the
patients is known as drug resistance.
• Resistance from drug of choice is because of different
mechanisms associated with respective drugs.
• First anti malarial drug resistance started in 1957 in
South East Asia region against chloroquinine.

5. DISEASE BURDEN….

6. DISTRIBUTION OF DRUG RESISTANT MALARIA

7. Drug Introduction “First” year
resistance
reported
Difference
(years)
Quinine 1632 1910 278
Chloroquine 1945 1957 12
Proguanil 1948 1949 1
Sulfadoxine-
pyrimethamine
1967 1967 <1
Mefloquine 1977 1982 5
Atovaquone 1996 1996 <1
Artemisinins 1971 1998 35
Development of drug resistance

8. REASONS FOR DEVELOPING RESISTANCE..??
 Unregulated or poorly administered antimalarial drug use.
 Combination drug therapy use without a complementary drug.
 The malaria parasite increases its capacity to repair the damage
caused by anti malarial drug gives it a higher chance of survival.
 Because the drug is more effective against the parasite at its later
stage of development, the parasite slowed down its growth so it
could survive longer in the younger stages.
 Long residual effect of antimalarial drugs.

10. DRUGS OF CHOICE…..
Combination therapy:
•Mefloquine+Artesunate
•Sulfadoxine/Pyrimethamine+Artesunate
•Lumefantrine+Artemether
Single-Agent Therapy:
•Chloroquine
•Amodiaquine
•Slfadoxine/Pyrimethamine
•Mefloquine
•Halofantrine
•Quinine
•Tetrayclin/Doxycyclin
•Atovaquone
•Primaquine
•Artemisine compounds

11. MECHANISMOF DRUGACTION
&
RESISTANCE DEVELOPMENT

12. Chloroquine, Amodiaquine,
Quinine, Quinidine,
Mefloquine, Primaquine
Lumefantrine and
Halofantrine.
•Theses drugs kills the
erythrocytic stage of
parasite.
•Primaquine also kills the
intrahepatic forms and
gametocytic stages.
QUINOLINE
DERIVATIVE
Choloroquine :
Mode of action-
Accumulating in plasmodium food vacuole leading to inhibition of
utilization of heme and producing complexes which are toxic to
plasmodium.
Resistance-
Among Chloroquine resistant parasites, there is a decrease in
accumulation of drug within the food vacuole.
Molecular basis-
•Mutation in the gene encoding the “Chloroquine Resistance
Transporter(Pf CRT)” in chromosome 7 (alteration K76T).
•In SEA S163R mutation(fourth transmembrane domain) was
found along with K76T.
Choloroquine :
Mode of action-
Accumulating in plasmodium food vacuole leading to inhibition of
utilization of heme and producing complexes which are toxic to
plasmodium.
Resistance-
Among Chloroquine resistant parasites, there is a decrease in
accumulation of drug within the food vacuole.
Molecular basis-
•Mutation in the gene encoding the “Chloroquine Resistance
Transporter(Pf CRT)” in chromosome 7 (alteration K76T).
•In SEA S163R mutation(fourth transmembrane domain) was
found along with K76T.
Amodiaquine :
It is similar to chloroquin and available in coformulation with
artesunate and treated in chloroquine resistance cases.
Side effects agranulocytosis and hepatotoxicity.
Molecular basis for resistance-
Pfcrt and Pfmdr1
Amodiaquine :
It is similar to chloroquin and available in coformulation with
artesunate and treated in chloroquine resistance cases.
Side effects agranulocytosis and hepatotoxicity.
Molecular basis for resistance-
Pfcrt and Pfmdr1

14. Quinine and Quinidine
Mode of action-
Depresses oxygen uptake
and carbohydrate
metabolism; disrupting Na/K
channel, intercalates into
DNA, disrupting parasites
replication and transcription.
Resistance –
Gene associated pfcrt1 ,
pfm dr1 and pfnhe 1
4-methanolquinolines
Quinoline - methanol
compound
Affective against all asexual
stages of different malarial
parasites.
Mode of action similar to CQ
Resistance-
Gene associated pfm dr1
Mefloquine
Similar to 4-
methanolquinolines in
structure. Used against
chloroquine & Mefloquine
resistant infections.
Mode of action same as CQ.
Resistance –
Gene associated pfcrt1 &
pfm dr1
Lumefantrine &
halofantrine

15. Mode of action-
It is a competitive inhibitor of
ubiquinol, specially inhibiting
the mitochondrial ETS at the
bc1 complex. Inhbition of bc1
activity results in a loss of
mitochondrial function.
Resistance-
Single nucleotide
polymorphism in the
cytochrome b gene
Atovaquone
Drugs include: Pyrimethamine,
Sulphonamides, Proguanil and
Dapsone.
Mode of action –
Drug synergistically target
enzymes involved in Folate
synthesis (DHFRase).
Resistance –
Due to mutational changes in
the plasmodium DHFRase
enzyme.
Resistance can be delayed by
using in combination with
Sulphonamide
Antifolates
Mode of action –
Sulfadoxine interferes with
bacterial folic acid synthesis
and growth via competitive
inhibition of para-
aminiobenzoic acid;
pyrimethamine inhibits
microbial dihydrofolate
reductase, resulting in
inhibition of tetrahydrofolic acid
synthesis
Resistance-
Sulfadoxine –
Pyrimethamine
Point mutations
in pfdhfr and pfdhps
associated genes.

16. Mode of action –
It act by binding iron, breaking
down peroxide bridges leading to
the generation of free radicals that
damage parasite proteins.
They act rapidly by clearly all blood
stages and gametocytes of
plasmodium species.
Resistance :
Pf kelch protein gene on
chromosome 13 (kelch13)
Artemisinin

17. Drug Mutations
Chloroquine pfcrt (K76T) codons:72-76; pfmdr1 (P. falciparum multidrug
resistance transporter 1) codon: 86Y/Y184/1246Y
Quinine pfcrt, pfmdr1, and pfnhe1 (P. falciparum sodium/proton exchanger 1)
Amodiaquine pfcrt, pfmdr1
Mefloquine Increased copy number of pfmdr1
Piperaquine Pfcrt :76T; pfmdr 1 codon: 86Y/Y184/1246Y
Lumefantrine Pfcrt codon: 72-76; pfmdr1 N86/184F/D1246 or increased copy
number
Atovaquone Single nucleotide polymorphisms in the cytochrome b gene
SP Point mutations in pfdhfr and pfdhps
Artemisinin Pf kelch protein gene on chromosome 13 (kelch13)
Sulfadoxine pfdhps: 437G/540E
Pyrimethamine pfdhfr : 51I/59R/108N- triplet mutation
P. vivax PvMDR1, pvdhfr and pvdhps
Genes involved in drug resistance

18. Response to therapyResponse to therapy
EVALUATION OF DRUG
RESISTANCEENDEMIC REGION:
EPIDEMIC REGION:
PCR

19. REFERENCES
Articles:
•Ingrid B Müller and John E Hyde ., Antimalarial Drugs: Modes of Action and
Mechanisms of Parasite Resistance; Future Microbiol. 2010;5(12)
•Carol Hopkins Sibley., Understanding drug resistance in malaria parasites:
Basic science for public health; Molecular & Biochemical Parasitology 195
(2014) 107–114
•Hiasindh Ashmi Antony and Subhash Chandra Parija., Antimalarial drug
resistance: An overview; Trop Parasitol. 2016 JanJun; 6(1): 30–41
•Liwang Cui aand et al., Antimalarial Drug Resistance: Literature Review and
Activities and Findings of the ICEMR Network; Am. J. Trop. Med. Hyg.,
93(Suppl 3), 2015, pp. 57–68
WWW :
•www.malariasite.com/drug-resistance/

20. THANKSTHANKS