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Dr
Laurent Dembele

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Current Organisation

Université des Sciences, des Techniques et des Technologies de Bamako

Current Job Title

Associate Professor

Biography

Publications

Authors:
Abdoulaye A. Djimde

Journal:
ACS Infectious Disease

Content:

In vitro and ex vivo cultivation of Plasmodium (P) falciparum has facilitated active research into the malaria parasite toward the quest for basic knowledge and the discovery of effective drug treatments. Such a drug discovery program is currently difficult for P. malariae simply because of the absence of in vitro and ex vivo cultivation system for its asexual blood stages supporting antimalarial evaluation. Despite availability of artemisinin combination therapies effective on P. falciparumP. malariae is being increasingly detected in malaria endemic countries. P. malariae is responsible for chronic infections and is associated with a high burden of anemia and morbidity. Here, we optimized and adapted ex vivo conditions under which P. malariae can be cultured and used for screening antimalarial drugs. Subsequently, this enabled us to test compounds such as artemether, chloroquine, lumefantrine, and quinine for ex vivo antimalarial activity against P. malariae.

Date:
2021-11-28

Authors:
Abdoulaye A Djimde

Journal:
J Antimicrob Chemother

Content:

Abstract

Objectives: To evaluate Plasmodium malariae susceptibility to current and lead candidate antimalarial drugs.

Methods: We conducted cross-sectional screening and detection of all Plasmodium species malaria cases, which were nested within a longitudinal prospective study, and an ex vivo assessment of efficacy of a panel of antimalarials against P. malariae and Plasmodium falciparum, both PCR-confirmed mono-infections. Reference compounds tested included chloroquine, lumefantrine, artemether and piperaquine, while candidate antimalarials included the imidazolopiperazine GNF179, a close analogue of KAF156, and the Plasmodium phosphatidylinositol-4-OH kinase (PI4K)-specific inhibitor KDU691.

Results: We report a high frequency (3%-15%) of P. malariae infections with a significant reduction in ex vivo susceptibility to chloroquine, lumefantrine and artemether, which are the current frontline drugs against P. malariae infections. Unlike these compounds, potent inhibition of P. malariae and P. falciparum was observed with piperaquine exposure. Furthermore, we evaluated advanced lead antimalarial compounds. In this regard, we identified strong inhibition of P. malariae using GNF179, a close analogue of KAF156 imidazolopiperazines, which is a novel class of antimalarial drug currently in clinical Phase IIb testing. Finally, in addition to GNF179, we demonstrated that the Plasmodium PI4K-specific inhibitor KDU691 is highly inhibitory against P. malariae and P. falciparum.

Conclusions: Our data indicated that chloroquine, lumefantrine and artemether may not be suitable for the treatment of P. malariae infections and the potential of piperaquine, as well as new antimalarials imidazolopiperazines and PI4K-specific inhibitor, for P. malariae cure.

Date:
2021-07-15

Authors:
Laurent Dembele, Devendra Kumar Gupta, Michelle Yi-Xiu Lim, Xiaoman Ang, Jeremy J. Selva, Kesinee Chotivanich, Chea Nguon, Arjen M. Dondorp, Ghislain M. C. Bonamy, Thierry T. Diagana, and Pablo Bifani.

Journal:
Antimicrob Agents Chemother

Content:

Date:
2018-04-26

Authors:
Laurent Dembele, Yaw Aniweh, Nouhoum Diallo, Fanta Sogore, Cheick Papa Oumar Sangare, Aboubecrin Sedhigh Haidara, Aliou Traore, Seidina A S Diakité, Mahamadou Diakite, Brice Campo, Gordon A Awandare, Abdoulaye A Djimde

Journal:
Journal of Antimicrobial Chemotherapy

Content:

Abstract

Objectives

To evaluate Plasmodium malariae susceptibility to current and lead candidate antimalarial drugs.

Methods

We conducted cross-sectional screening and detection of all Plasmodium species malaria cases, which were nested within a longitudinal prospective study, and an ex vivo assessment of efficacy of a panel of antimalarials against P. malariae and Plasmodium falciparum, both PCR-confirmed mono-infections. Reference compounds tested included chloroquine, lumefantrine, artemether and piperaquine, while candidate antimalarials included the imidazolopiperazine GNF179, a close analogue of KAF156, and the Plasmodium phosphatidylinositol-4-OH kinase (PI4K)-specific inhibitor KDU691.

Results

We report a high frequency (3%–15%) of P. malariae infections with a significant reduction in ex vivo susceptibility to chloroquine, lumefantrine and artemether, which are the current frontline drugs against P. malariae infections. Unlike these compounds, potent inhibition of P. malariae and P. falciparum was observed with piperaquine exposure. Furthermore, we evaluated advanced lead antimalarial compounds. In this regard, we identified strong inhibition of P. malariae using GNF179, a close analogue of KAF156 imidazolopiperazines, which is a novel class of antimalarial drug currently in clinical Phase IIb testing. Finally, in addition to GNF179, we demonstrated that the Plasmodium PI4K-specific inhibitor KDU691 is highly inhibitory against P. malariae and P. falciparum.

Conclusions

Our data indicated that chloroquine, lumefantrine and artemether may not be suitable for the treatment of P. malariae infections and the potential of piperaquine, as well as new antimalarials imidazolopiperazines and PI4K-specific inhibitor, for P. malariae cure.

Date:
2021-05-22

Authors:
Dinkorma T Ouologuem 1, Laurent Dembele 1, Antoine Dara 1, Aminatou K Kone 1, Nouhoum Diallo 1, Cheick P O Sangare 1, Fatoumata I Ballo 1, François Dao 1, Siaka Goita 1, Aboubecrin S Haidara 1, Aliou Traore 1, Amadou B Niangaly 1, Souleymane Dama 1, Sekou Sissoko 1, Fanta Sogore 1, Jacob N Dara 1, Yacouba N Barre 1, Amadou Daou 1, Fatoumata Cisse 1, Ousmaila Diakite 1, Diagassan Doumbia 1, Sekou Koumare 1, Bakary Fofana 1, Fatalmoudou Tandina 1, Daman Sylla 1, Adama Sacko 1, Mamadou Coulibaly 1, Mamadou M Tekete 1, Amed Ouattara 1 2, Abdoulaye A Djimde 1

Journal:
Antimicrob Agents Chemother

Content:

The discovery and development of transmission-blocking therapies challenge malaria elimination and necessitate standard and reproducible bioassays to measure the blocking properties of antimalarial drugs and candidate compounds. Most of the current bioassays evaluating the transmission-blocking activity of compounds rely on laboratory-adapted Plasmodium strains. Transmission-blocking data from clinical gametocyte isolates could help select novel transmission-blocking candidates for further development. Using freshly collected Plasmodium falciparum gametocytes from asymptomatic individuals, we first optimized ex vivo culture conditions to improve gametocyte viability and infectiousness by testing several culture parameters. We next pre-exposed ex vivo field-isolated gametocytes to chloroquine, dihydroartemisinin, primaquine, KDU691, GNF179, and oryzalin for 48 h prior to direct membrane feeding. We measured the activity of the drug on the ability of gametocytes to resume the sexual life cycle in Anopheles after drug exposure. Using 57 blood samples collected from Malian volunteers aged 6 to 15 years, we demonstrate that the infectivity of freshly collected field gametocytes can be preserved and improved ex vivo in a culture medium supplemented with 10% horse serum at 4% hematocrit for 48 h. Moreover, our optimized drug assay displays the weak transmission-blocking activity of chloroquine and dihydroartemisinin, while primaquine and oryzalin exhibited a transmission-blocking activity of ~50% at 1 μM. KDU691 and GNF179 both interrupted Plasmodium transmission at 1 μM and 5 nM, respectively. This new approach, if implemented, has the potential to accelerate the screening of compounds with transmission-blocking activity.

Date:
2022-12-20

Authors:
Adeline C.Y.Chua, Abhishek Ananthanarayanan, Jessica Jie Ying Ong, Jen Yi Won, AndyYip, Nisha Hari Singh, Yinghua Qu, Laurent Dembele, Michael McMillian, Ratawan Ubalee, Silas Davidson, Anchalee Tungtaeng, Rawiwan Imerbsin, Kapish Gupta, Chiara Andolina, FanLee, Kevin S-W Tan, François Nosten, Bruce Russell, Amber Lange, Thierry T. Diagana, Laurent Rénia, Bryan K.S.Yeung, HanryYudi, Pablo Bifani*.

Journal:
Biomaterials

Content:

Date:
2019-05-22

Authors:
Devendra Kumar Gupta†, Laurent Dembele†, Annemarie Voorberg-van der Wel, Guglielmo Roma, Andy Yip, Vorada Chuenchob, Niwat Kangwanrangsan, Tomoko Ishino, Ashley M Vaughan6, Stefan H Kappe, Erika L Flannery, Jetsumon Sattabongkot, Sebastian Mikolajczak, Pablo Bifani, Clemens HM Kocken, Thierry Tidiane Diagana*.

Journal:
eLife

Content:

Date:
2019-05-16

Authors:
Laurent Dembélé 1 2 3, Jean-François Franetich 1, Valérie Soulard 1, Nadia Amanzougaghene 1, Shahin Tajeri 1, Teun Bousema 4, Geert-Jan van Gemert 4, Roger Le Grand 5, Nathalie Dereuddre-Bosquet 5, J Kevin Baird 6 7, Dominique Mazier # 1, Georges Snounou # 1 5

Journal:
Antimicrob Agents Chemothe

Content:

For a long while, 8-aminoquinoline compounds have been the only therapeutic agents against latent hepatic malaria parasites. These have poor activity against the blood-stage plasmodia causing acute malaria and must be used in conjunction with partner blood schizontocidal agents. We examined the impacts of one such agent, chloroquine, upon the activity of primaquine, an 8-aminoquinoline, against hepatic stages of Plasmodium cynomolgiPlasmodium yoeliiPlasmodium berghei, and Plasmodium falciparum within several ex vivo systems-primary hepatocytes of Macaca fascicularis, primary human hepatocytes, and stably transformed human hepatocarcinoma cell line HepG2. Primaquine exposures to formed hepatic schizonts and hypnozoites of P. cynomolgi in primary simian hepatocytes exhibited similar 50% inhibitory concentration (IC50) values near 0.4 μM, whereas chloroquine in the same system exhibited no inhibitory activities. Combining chloroquine and primaquine in this system decreased the observed primaquine IC50 for all parasite forms in a chloroquine dose-dependent manner by an average of 18-fold. Chloroquine also decreased the primaquine IC50 against hepatic P. falciparum in primary human hepatocytes, P. berghei in simian primary hepatocytes, and P. yoelii in primary human hepatocytes. Chloroquine had no impact on primaquine IC50 against P. yoelii in HepG2 cells and, likewise, had no impact on the IC50 of atovaquone (hepatic schizontocide) against P. falciparum in human hepatocytes. We describe important sources of variability in the potentiation of primaquine activity by chloroquine in these systems. Chloroquine potentiated primaquine activity against hepatic forms of several plasmodia. We conclude that chloroquine specifically potentiated 8-aminoquinoline activities against active and dormant hepatic-stage plasmodia in normal primary hepatocytes but not in a hepatocarcinoma cell line.

Date:
2020-12-16

Authors:
Désiré N, Ngo Y, Franetich JF, Laurent Dembele, Mazier D, Vaillant JC, Poynard T, Thibault V.

Journal:
J Viral Hepat

Content:

Date:
2015-09-22

Authors:
Laurent Dembélé, Jean-François Franetich, Audrey Lorthiois, Audrey Gego, Anne-Marie Zeeman, Clemens H M Kocken, Roger Le Grand, Nathalie Dereuddre-Bosquet, Geert-Jan van Gemert, Robert Sauerwein, Jean-Christophe Vaillant, Laurent Hannoun, Matthew J Fuchter, Thierry T Diagana, Nicholas A Malmquist, Artur Scherf, Georges Snounou & Dominique Mazier.


Journal:
Nature Medicine

Content:

Date:
2014-02-09

Authors:
Laurent Dembele, Ang X, Chavchich M, Bonamy GMC, Selva JJ, Lim MY, Bodenreider C, Yeung BKS, Nosten F, Russell BM, Edstein MD, Straimer J, Fidock DA, Diagana TT, Bifani.


Journal:
Scientific Reports

Content:

Date:
2017-05-24

Authors:
Devendra Kumar Gupta,#1,2,† Laurent Dembele,#2,3,† Annemarie Voorberg-van der Wel,4 Guglielmo Roma,5 Andy Yip,2 Vorada Chuenchob,6 Niwat Kangwanrangsan,7 Tomoko Ishino,8 Ashley M Vaughan,6 Stefan H Kappe,6 Erika L Flannery,6 Jetsumon Sattabongkot,9 Sebastian Mikolajczak,1,6 Pablo Bifani,2,10,11 Clemens HM Kocken,4 and Thierry Tidiane Diagana1,2

Journal:
eLife.

Content:

Plasmodium vivax hypnozoites persist in the liver, cause malaria relapse and represent a major challenge to malaria elimination. Our previous transcriptomic study provided a novel molecular framework to enhance our understanding of the hypnozoite biology (Voorberg-van der Wel A, et al., 2017). In this dataset, we identified and characterized the Liver-Specific Protein 2 (LISP2) protein as an early molecular marker of liver stage development. Immunofluorescence analysis of hepatocytes infected with relapsing malaria parasites, in vitro (P. cynomolgi) and in vivo (P. vivax), reveals that LISP2 expression discriminates between dormant hypnozoites and early developing parasites. We further demonstrate that prophylactic drugs selectively kill all LISP2-positive parasites, while LISP2-negative hypnozoites are only sensitive to anti-relapse drug tafenoquine. Our results provide novel biological insights in the initiation of liver stage schizogony and an early marker suitable for the development of drug discovery assays predictive of anti-relapse activity.

Date:
2019-05-16

Authors:
Laurent Dembele, Audrey Gego , Anne-Marie Zeeman, Jean-François Franetich, Olivier Silvie, Armelle Rametti, Roger Le Grand, Nathalie Dereuddre-Bosquet, Robert Sauerwein, Geert-Jan van Gemert, Jean-Christophe Vaillant, Alan W. Thomas, Georges Snounou , Clemens H. M. Kocken , Dominique Mazier.

Journal:
PLoS One

Content:

Date:
2011-03-31

Authors:
Laurent Dembele* Devendra Kumar Gupta Bamaprasad Dutta Adeline C.Y. Chua Siu Kwan Sze Pablo Bifani.

Journal:
PROTEOMICS

Content:

Date:
2019-08-24

Authors:
Annemarie M. Voorberg-van der Wel 1, Anne-Marie Zeeman1, Ivonne G. Nieuwenhuis1, Nicole M. van der Werff1, Els J. Klooster1, Onny Klop1, Lars C. Vermaat1, Devendra Kumar Gupta2, Laurent Dembele2,3, Thierry T. Diagana2 & Clemens H.M. Kocken1*

Journal:
COMMUNICATIONS BIOLOGY

Content:

Plasmodium vivax malaria is characterized by repeated episodes of blood stage infection (relapses) resulting from activation of dormant stages in the liver, so-called hypnozoites. Transition of hypnozoites into developing schizonts has never been observed. A barrier for studying this has been the lack of a system in which to monitor growth of liver stages. Here, exploiting the unique strengths of the simian hypnozoite model P. cynomolgi, we have developed green-fluorescent (GFP) hypnozoites that turn on red-fluorescent (mCherry) upon activation. The transgenic parasites show full liver stage development, including merozoite release and red blood cell infection. We demonstrate that individual hypnozoites actually can activate and resume development after prolonged culture, providing the last missing evidence of the hypnozoite theory of relapse. The few events identified indicate that hypnozoite activation in vitro is infrequent. This system will further our understanding of the mechanisms of hypnozoite activation and may facilitate drug discovery approaches.

Date:
2020-01-03