New mechanism for malaria parasite resistance to artemisinin
10 May 2010
Researchers from CNRS, INSERM and Toulouse University Hospital
have demonstrated how the malaria parasite Plasmodium falciparum
is able to circumvent the action of artemisinin and its
derivatives, which are today the first-line drugs used to treat this
This study will enable a clearer understanding of the mechanisms of
resistance to antimalarial drugs and the testing of novel
therapeutic strategies in a context where the drug resistance of
parasites is of increasing concern. Published in the May 2010 issue
of Antimicrobial Agents and Chemotherapy , this work was
carried out in collaboration with the US National Institutes for
Malaria kills nearly a million people each year throughout the
world. There is no vaccine against this infectious disease which is
caused by a parasite of the Plasmodium genus and propagated
via the bites of certain mosquitoes. Plasmodium falciparum
is the most pathogenic species, causing a high death rate. It
accounts for more than 80% of cases of human malaria and is present
in the tropical regions of Africa, Latin America and Asia.
For the past ten years, artemisinin (ART), a substance extracted
from a Chinese plant, has become the first-line drug for malaria,
particularly since other compounds have lost their efficacy. Its
action against all strains of Plasmodium falciparum,
including those resistant to other antimalarials, is the principal
advantage of ART. Furthermore, its antimalarial activity is very
rapid, and it has few adverse effects.
Combining artemisinin with another antimalarial agents
considerably reduces the risk of onset of resistance. For this
reason, the WHO has for several years been recommending the
systematic use of this compound and its derivatives in combination
with other antimalarial agents. Artermisinin-based Combination
Therapies (ACT) now constitute the most effective treatment for
malaria (1), achieving a 95% cure rate.
However, in July 2009, the first cases of resistance to
artesunate, the ART derivative most widely used in ACT, were
observed among patients in South-East Asia. It has therefore become
essential to determine how Plasmodium falciparum is able to
circumvent the action of ART and its derivatives.
A team led by Françoise Benoit-Vical, senior INSERM researcher in
the CNRS Laboratoire de Chimie de Coordination, isolated
ART-resistant strains at the end of 2009. The team obtained a strain
of Plasmodium falciparum that was resistant to this
compound and some of its derivatives, and the first to be adapted to
in vitro culture.
The team demonstrated that this ART-resistant strain was able to
survive in the presence of ART at a dose that was 7000 times higher
than the IC50 on susceptible strains. In addition, this experimental
strain shared certain traits with the resistant strains found in the
The researchers also identified and characterized a new mode of
parasite resistance. To evade the action of ART, Plasmodium
falciparum arrested its development and entered a so-called
state of quiescence. It thus functioned at a slow metabolic rate
until the drug was eliminated. This quiescence phenomenon was only
observed in parasites at the ring stage (the first stage of the
parasitic cycle in red blood cells). In parallel, an analysis
performed with a National Institutes of Health team suggested that
the expression of some proteins involved in the cell cycle of
Plasmodium falciparum might be modified in resistant strains.
Further studies are planned to identify the genes responsible for
the acquisition of ART resistance.
The scientists were thus able to demonstrate a novel resistance
mechanism and now benefit from an important tool that will allow a
clearer understanding of the mechanisms of resistance to
antimalarial drugs; this will also enable the testing of different
therapeutic options (new compounds, new therapeutic combinations,
new targets, etc.).
Witkowski B, Lelièvre J, López Barragán MJ, Laurent V, Su XZ,
Berry A, Benoit-Vical F. Increased tolerance to artemisinin in
Plasmodium falciparum is mediated by a quiescence mechanism.
Antimicrobial Agents and Chemotherapy. May 2010.