Actualité scientifique
Scientific news
© IRD / B. Vergnes
© IRD / JP Gonzalez
Leishmaniasis is a serious
parasitic disease with
several forms, cutaneous
mucocutaneous or
visceral, respectively
causing skin sores,
ulceration and internal
damage. The visceral form
can be fatal if no treatment
is given. These diseases
are endemic in more than
98 countries across the
world, most of them
developing countries, and
350 million people are
exposed to them. The
protozoan pathogens,
responsible, from the
genus Leishmania, are
transmitted to humans or
other mammals by the bite
of a sand fly, Phlebotomus.
Medications exist,
including antimony, the
one most commonly used,
but their efficacy is
diminishing owing to the
emergence of resistant
parasites.
Nevertheless new hope is
on the horizon for treating
this much-neglected
disease. IRD scientist and
their research partners1
recently identified the key
role of nicotinamidase, an
enzyme2 in the parasite
Leishmania, essential for
its survival but which does
not exist in humans. The
pathogen is incapable of
developing in mammals In
the absence of this
enzyme. Specific targeting
of this enzyme could lead
to more effective ways of
controlling this neglected
tropical disease.
© IRD - UCAD
September 2011
New therapeutic target
against leishmaniasis
© IRD – Laboratoire P2 Montpellier
N° 383
Actualidad cientifica
The sandfly Phlebotoma transmits the parasite Leishmania to humans through its bite (top right, infected cells of the immune system) which causes skin sores
(here in Tunisia), mucosal ulceration or visceral damage.
Leishmaniasis is a much-neglected tropical disease,
in a similar way to Chagas disease or sleeping
sickness. Without treatment, the most severe form
of the parasitic infection generated –visceral leishmaniasis– proves fatal. The different forms affect
16 million people in the world, mainly in the developing countries. The options for treatment are often
dictated by cost. For this reason the relatively inexpensive antimony derivatives are the most commonly
used antileishmanials, aside from their efficacy.
However, their curative effect is weakening owing to
the emergence of resistant strains. It is becoming
urgent to develop new, inexpensive antileishmanial
agents that are more effective and have low toxicity.
Outdated treatments
The medications currently used present a whole
combination of drawbacks. Treatments are long,
toxic and relapse is highly common. Most of them
date back to research conducted in the 1950s. In
India, the situation is becoming critical following the
emergence of resistant strains of the parasite,
where in some regions, failure of classic treatments
can be as high as 60% in patients who have never
previously been treated. In this context, control of
the endemic parasitic disease depends on the discovery of new means of prevention and treatments,
affordable for the people concerned. Scientists are
developing various measures for developing a
vaccine for humans and devise the medications of
the future.
New approach, new drug target
The classical way of searching for antiparasitic
drugs consists in using in vitro techniques to screen
the antiparasitic activity of natural substances or
medications initially applied for a completely different
use. Thus the active molecules against leishma-
For further information
niasis have previously been isolated from natural
plant substances, like quinolines*.
A new therapeutic pathway is being traced thanks to
a new approach. While seeking the nutritional
factors which enable Leishmania to adapt to the
host’s internal environment, IRD researchers and
their partners 1 characterized a new therapeutic
target: an enzyme2, nicotinamidase, which plays a
key role in the parasite’s cellular development. The
research team identified this compound in Leishmania and demonstrated its importance for the
pathogen’s survival. Nicotinamidase enables it to
assimilate vitamin B3 (nicotinamide), essential for
the synthesis of a substance vital for all cells,
NAD+3. And, crucially, this enzyme does not occur in
mammals, thereby precluding any risks of crossactivity in humans. Joint research with a structural
biochemistry team in Montpellier was successful in
determining the structure of this enzyme isolated
from the parasite. This has opened the way for
chemists to synthesize specific inhibitors of that
enzyme that will hold back the parasite’s proliferation in the host.
Four of the five continents
affected
Leishmaniasis is transmitted by a single bite from its
vector, the sandfly Phlebotoma. It comprises three
different forms: cutaneous, mucocutaneous and
visceral, the most serious. These parasitic infections
rage over extensive areas of the globe, affecting 98
countries, in all parts of the world, except Oceania,
and 350 million people are exposed to the risk of
contracting it. An estimated 2 to 2.5 million new
cases arise each year, of whom 500 000 people are
struck by the visceral form of the disease.
Dogs and wild Canidae are the major reservoirs of
this disease which is rife mainly around the Mediterranean Basin. In these areas, strongly endemic for
canine leishmaniasis, incidence in humans nevertheless remains quite low. The disease is an
increasingly important problem in Southern Europe
with the spread of the AIDS pandemic and a growing
number of Leishmania/HIV co-infections occurring.
But the cause for concern is even more extreme for
public health in other parts of the world. Especially so
in India, Brazil and the Sudan (zones endemic to L.
donovani/chagasi), where the past few decades have
seen fatal epidemics leaving thousands of victims.
Contacts
Denis Sereno,
researcher at the IRD
Tel.: +33 (0)4 67 41 63 08
denis.sereno@ird.fr
Baptiste Vergnes,
engineer of research at the IRD
Tél. : +33 (0)4 67 41 63 08
baptiste.vergnes@ird.fr
UMR Maladies infectieuses et vecteurs :
écologie, génétique, évolution et
contrôle – MIVEGEC (IRD / CNRS /
Université Montpellier 1)
Address
IRD Centre de Montpellier
911 avenue Agropolis
BP 64501
34394 Montpellier cedex 5
Gilles Labesse,
researcher at the CNRS
Tel.: +33 (0)4 67 41 77 12
Gilles.Labesse@cbs.cnrs.fr
These new investigations have brought new hope of
treatment for the several million sufferers. Nicotinamidase, the enzyme the research team characterized and absent from mammals, turns out to be
particularly promising for more effectively fighting
this neglected tropical disease. Scientists will now
be better armed to develop inhibitors that specifically target Leishmania and, more generally, the
other parasites of the Trypanosomatidae family.
Address
Centre de Biochimie Structurale
29, rue de Navacelles
F-34090 Montpellier Cedex
References
Gazanion E, Garcia D, Silvestre R,
Gérard C, Guichou J, Labesse G,
Seveno M, Cordeiro-Da-Silva A, Ouaissi
A, Sereno Denis, Vergnes Baptiste.
The Leishmania nicotinamidase is
essential for NAD+ production and
parasite proliferation. Molecular
Microbiology, 2011.
doi:10.1111/j.1365-2958.2011.07799.x
*see scientific bulletin n°216 - De nouvelles molécules particulièrement actives contre les leishmanies and n° 335 - La leishmaniose - des plantes medications pour une maladie négligée.
Gazanion E., Vergnes Baptiste,
Seveno M., Garcia D., Oury B.,
Ait-Oudhia K., Ouaissi A., Sereno Denis.
In vitro activity of nicotinamide/
antileishmanial drug combinations.
Parasitology International, 2011,
60 (1), p. 19-24. doi:10.1016/j.
parint.2010.09.005
Copy editor – Gaëlle Courcoux - DIC, IRD
Translation – Nicholas FLAY
1. These investigations were conducted in partnership with the University of Porto in Portugal, Universities of Montpellier 1 and 2, the CNRS
and INSERM.
Key words
Leishmaniasis, parasite, treatment
2. An enzyme is a compound which favours and accelerates a chemical reaction in the cell.
Leishmania parasites (whose DNA shows up in red, centre) infect cells of the human immune system (right) and other mammals such as dogs.
Coordination
Gaëlle Courcoux
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View the IRD photos concerning this article,
copyright free for the press, on:
www.indigo.ird.fr
Graphic design and layout
Laurent Corsini
© IRD / B. Vergnes
© IRD / A. Fournet
© IRD / A. Fournet
3. Nicotinamide adenine dinucleotide (NAD+) is a cofactor, meaning a chemical substance whose presence is necessary for the biological
activity of an enzyme for a particular reaction to proceed.
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