Louis Maes emeritus with assignment

Research Louis Maes

Research team

Expertise

- Antioxidant evaluation of pure compounds and extracts. - Integrated antimicrobial (bacteria, fungi, yeasts and parasites) screening and profiling of pure compounds and extracts, microbiological analysis of pharmaceuticals, cosmetics, and raw materials and animal models for evaluation of antimicrobial activity.

Research services to complete a project entitled "21st Century Treatments for Sustainable Elimination of Leishmaniasis – Part 2" (LeishNCE2). 01/01/2022 - 31/12/2024

Abstract

The collaboration with DNDi is aimed at providing a solid proof-of-concept in in vitro and animal models for the treatment of leishmaniasis with current (pre-)clinical leads and/or with a combination of leads and current reference antileishmanial drugs. Services to support DNDi discovery and development projects will cover in vitro monotherapy profiling against a panel of (resistant) strains, in vivo evaluation in mouse and/or hamster efficacy models including both monotherapy and combination therapy with PK analysis, evaluation of antiparasitic killing kinetics, and evaluation in immunocompromised animal models.

Researcher(s)

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Project type(s)

  • Research Project

Preclinical progression of novel anti-trypanosomal nucleoside 'lead' series towards veterinary application. 01/05/2020 - 31/08/2021

Abstract

Within ongoing collaborative research with the Lab. of Medicinal Chemistry (UGent), a series of novel nucleoside analogues was identified to have potent and selective in vitro activity against African Trypanosomes, which was also confirmed in vivo in an acute and a chronic mouse model of Trypanosoma brucei. A basic dataset supporting early preclinical exploration is already available: oral availability, metabolic stability, blood-brain barrier passage, cidal and curative potential and mechanism of action. Project valorization potential must currently be situated in the veterinary application area in view of its economical and societal impact, and much less in the human application. In order to formally upgrade this project to 'drug development candidate' status, additional preclinical exploration is required to reach a go / no-go decision and trigger a commitment of a committed public-private partnership (GALVmed). In line with their preferred target product profile (TPP), the proposed research will involve in vitro and in vivo pharmacology extended to the animal trypanosome species, absorption and elimination pharmacokinetics after oral and parenteral (single dose) administration, in vitro metabolic half-life in the target animal species (cattle, horse), genotoxicity (Ames test) and short term (2w) repeated-dose toxicity in mice.

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Project type(s)

  • Research Project

Characterizing the bone marrow as a parasitological niche responsible for antileishmanial treatment failure. 01/01/2019 - 31/12/2022

Abstract

Visceral Leishmaniasis (VL) or Kala-Azar is a neglected tropical disease caused by Leishmania parasites that are transmitted by sand flies. Paromomycin (PMM) is used to treat VL patients but was experimentally shown to rapidly induce resistance when applied as a single therapy. We have recently observed that parasites overcome elimination by PMM by hiding in the bone marrow (BM) from where the host can be recolonized. Using combined bioluminescent/fluorescent L. infantum reporter lines with differential susceptibility to PMM, this project will make an in depth analysis of the different cell types in the BM that are infected with L. infantum. Parasite survival in various BM cell types will be evaluated to identify potential sanctuary cells. Parasite isolates from the BM of mice and human patients will be used to explore the acquisition of PMM-resistance in relation to parasite virulence. Infectivity for macrophages and transmissibility by sand flies will serve as indicators for the likelihood of posttreatment parasites to spread. Parallels with treatment of myeloid leukemia, indicate that modulating a specific pathway in hematopoiesis that regulates the BM cellular composition could enhance the efficiency of chemotherapy for VL. Collectively, the proposed multidisciplinary approach will improve our understanding of the complex interactions between the parasite, its host and the drug and will allow the formulation of recommendations for improved treatment interventions.

Researcher(s)

Research team(s)

Project type(s)

  • Research Project

The role of parasite sanctuary sites and interaction with Kupffer cells in treatment failure of Visceral Leishmaniasis. 01/10/2018 - 30/09/2020

Abstract

Visceral Leishmaniasis (VL) or Kala-Azar is a neglected tropical disease caused by Leishmania parasites that are able to survive inside macrophages. Miltefosine is an oral drug used to treat VL patients but is increasingly failing to permanently clear parasites from the patient. Parasites from these relapse patients do not seem to display an increased resistance to the drug but are able to modify the immune system to promote survival inside macrophages even in conditions where the drug is administered. The impact of drug treatment on parasite survival will be evaluated in various tissues using molecular and imaging technologies in rodent models of VL following a natural parasite transmission. Combination of this information with the quantification of drug levels in these tissues, will allow to pinpoint in which tissues parasites are most likely to survive drug treatment. The expression of genes following infection and drug treatment will be analyzed inside infected liver macrophages (Kupffer cells, KCs) in order to understand how parasites from relapsed patients can survive inside host cells. Using transgenic mouse models, this research will allow to evaluate the impact of KCs and KC gene expression on infection and treatment outcome. Collectively, the proposed multidisciplinary approach will improve our understanding of the complex interactions between the parasite, its host and the drug and will allow the formulation of recommendations for improved treatment interventions.

Researcher(s)

Research team(s)

Project type(s)

  • Research Project

Comprehensive Liquid Chromatography - Ion Mobility - Quadrupole-Time-of-Flight Mass Spectrometry for innovative metabolomics. 01/05/2018 - 30/04/2021

Abstract

The requested infrastructure (comprehensive liquid chromatograph-ion mobility-quadrupole time of flight mass spectrometer LCxLC-IM-QTOFMS) combines several state-of-the-art technologies into one platform which aims at bringing metabolomics research to the next level. As such, the infrastructure will deliver a combined five-dimension separation and detection technology, the first of its kind in Belgium. This instrument will be dedicated to metabolomics research, the science of endogenous metabolites in cells, tissues or organisms. The infrastructure will be able to optimally separate, detect and identify the very broad and complex chemical space of metabolites ranging from very polar (e.g. amino acids) to non-polar (e.g. lipids and hormones) at low nanomolar concentration range. Within UA, there is a growing need to combine the currently scattered efforts in metabolomics, an Emerging Frontline Research Domain in the UA research scene. Research ranges from drug discovery (mode of action and pharmacokinetic profiling), biomarker and toxicity studies to advanced data-analysis and systems biology approaches, but a dedicated metabolomics infrastructure to strengthen these studies is currently missing. As such, the investment in a core facility together with the gathering of nine research groups from five departments and two faculties would centralize the metabolomics research. This will position UA as a key player in the academic metabolomics research in the BeNeLux and worldwide.

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  • Research Project

Towards new concepts in anti-Leishmania treatment by modifying the interplay between sand fly transmitted parasites and the host innate immune system 01/01/2018 - 31/12/2021

Abstract

Leishmaniasis is a major neglected parasitic disease with a broad range of clinical manifestations including the lethal visceral disease. New drug discovery initiatives are essential given the serious adverse effects of current treatments and/or the increasing threat of drug resistance development. The present project aims to contribute towards novel concepts on intervention strategies that could bypass some problems relating to drug failure. Through the establishment of a sand fly colony, host-parasite interactions such as parasite virulence, disease-associated immunity and pathology, and treatment efficacy will be studied in laboratory rodent models that include the insect vector. The vector component will also allow improved antileishmanial lead characterization, drug resistance research and adaptation of clinical isolates to in vitro and in vivo laboratory models enabling improved monitoring of treatment efficacy in the field. This study will explore the interplay of host immune cells (neutrophils and monocytes) with recent clinical isolates and laboratory strains showing significant differences in virulence that arise from the acquisition of drug resistance. Responses will be studied by using a state-of-the art kinomics platform, that allows a straightforward acquisition of phenotypic fingerprints of intracellular kinase activation. This will provide cutting-edge information on the parasite-host interplay and on inflammation in general. Knowing that neutrophils have been ascribed infection-promoting activities, selective targeting of innate immune cell function will be explored as a complementary asset to control parasitic infections. This has not yet been explored, although anticipated to be much less prone to the development of resistance mechanisms. This approach could possibly also support the identification of novel drug or vaccine targets.

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  • Research Project

Modified 7-deazapurine nucleoside analogues for the treatment of human African trypanosomiasis: towards a strong proof-of-concept. 01/01/2018 - 31/12/2021

Abstract

Human African trypanosomiasis (HAT) or sleeping sickness is a parasitic disease transmitted by tsetse flies with a relatively benign haemolymphatic followed by a lethal encephalitic stage. Treatment is increasingly compromised by emergence of drug resistance in addition to the known toxicity of current drugs. In response to this medical need, our previous hit-finding campaign identified nucleoside analogues that are highly potent and selective against trypanosomes in vitro and fully curative in vivo after oral administration (50 mg/kg for 5 days) in an acute mouse model. This project will make a structure-activity relationship by expanding two novel compound series to further optimize potency and to make drug uptake less dependent on a single transporter that is prone to resistance development. The chemical synthesis will be combined with detailed evaluation of compound efficacy using state-of-the art methodologies, including natural transmission models and in vivo bioluminescent imaging to assess overall impact of treatment. Aiming to comply with the desired target product profile for such drugs, potency will be evaluated in acute and chronic infections with cerebral involvement. Most promising compounds will be subjected to identification of the action mechanism using loss-of-function and protein biochemical approaches. Collectively, this project aims at providing a convincing proof-of-concept for the use of nucleoside analogues for the treatment of this neglected disease.

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  • Research Project

Exploring and targeting the kinome of immune cells exposed to African trypanosomes. 01/01/2018 - 31/12/2021

Abstract

Neutrophils and macrophages are cells of the innate immune system of the mammalian host with a range of potential effector functions against pathogens. These cells are rapidly recruited to sites of parasite infection. Counterintuitively, neutrophils favor the onset of parasite infections as we have described for sleeping sickness parasites (Trypanosoma brucei sp.) inoculated by the bites of tsetse flies. Indeed, selective neutrophil removal or genetic conditions resulting in lower neutrophil levels in the blood yield a higher level of resistance to trypanosome infection. Monocytes on the other hand are activated to differentiate into activated macrophages that contribute to parasite control in the early stage of infection. The differential impact of neutrophils and macrophages suggests that specific inhibition of neutrophil functions could result in higher levels of resistance to infection. This project will compare the responses of neutrophils and monocytes to parasite presence by capturing their kinase activity fingerprints. Kinase targets in cell type specific and common responsive pathways will be identified. Kinase inhibitors from commercially available or proprietary collections will be used to selectively inhibit the parasite-induced responses and to evaluate the impact on parasite infection. Collectively, this project will forward our understanding of early trypanosome transmission and is directed at revealing novel transmission-blocking concepts and strategies.

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  • Research Project

Research Collaboration VL-MOA/MOR. 18/12/2017 - 31/12/2021

Abstract

DNDi has screened a number of non-proprietary compounds that could potentially be used for the treatment of visceral leishmaniasis (VL). DNDi and research partners have further optimised these quality compounds to discover lead compounds or preclinical development candidates. DNDi and the research partners are interested in exploring the mechanisms of action (MOA) of these compounds with regard to Leishmania parasites and resistance (MOR) of the parasites to these compounds. The research will be conducted by the network of research collaborator(s) and may include in vitro and in vivo resistance selection, whole genome sequencing, metabolomics, genetic modification including up-and-down regulation, RIT-seq, PLATO, DiCRE, CISPR/Cas 9 and other applicable methods.

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Project type(s)

  • Research Project

Exploring and targeting the kinome of immune cells exposed to protozoan parasites. 01/10/2017 - 30/09/2021

Abstract

Neutrophils and macrophages are cells of the innate immune system of the mammalian host with a range of potential effector functions against pathogens. These cells are rapidly recruited to sites of parasite infection. Counterintuitively, neutrophils favor the onset of parasite infections as we have described for sleeping sickness parasites (Trypanosoma brucei sp.) inoculated by the bites of tsetse flies. Indeed, selective neutrophil removal or genetic conditions resulting in lower neutrophil levels in the blood yield a higher level of resistance to trypanosome infection. Monocytes on the other hand are activated to differentiate into M1 macrophages that contribute to parasite control in the early stage of infection. The differential impact of neutrophils and macrophages suggests that specific inhibition of neutrophil functions could result in higher levels of resistance to infection. This project will compare the responses of neutrophils and monocytes to parasite presence by capturing their kinase activity fingerprints. Kinase targets in cell type specific and common responsive pathways will be identified. Kinase inhibitors from commercially available or proprietary collections will be used to selectively inhibit the parasite-induced responses and to evaluate the impact on parasite infection. Collectively, this project will forward our understanding of early trypanosome transmission and is directed at revealing novel transmission-blocking concepts and strategies.

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Project type(s)

  • Research Project

Initiatives towards valorisation of antifungal drugs 07/09/2017 - 31/08/2018

Abstract

This project is a continuation of a former project that focused on the in depth evaluation of novel benzodiazepine antifungal compounds that proved to be highly active against dermatophyte infections. However, when focusing on the medical needs in the field, onychomycosis remains the sole infection within the broader group of dermatomycoses that could represent a market potential. This project specifically focuses on the potential of the preferred hit compound in a onychomycosis model with particular focus on model development and permeation characteristics through the nail after topical administration and in the nail bed after oral administration.

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  • Research Project

A drug discovery with a particular focus on tropical protozoa (leishmaniasis, malaria, sleeping sickness and Chagas disease) and mycotic infections (yeasts, dermatophytes and fungi). 01/01/2017 - 31/12/2021

Abstract

This project represents a formal research agreement between UA and on the other hand DNDI. UA provides DNDI research results mentioned in the title of the project under the conditions as stipulated in this contract.

Researcher(s)

Research team(s)

Project type(s)

  • Research Project

Exploring and targeting the kinome of immune cells exposed to protozoan parasites. 01/01/2017 - 31/12/2017

Abstract

Neutrophils and macrophages are cells of the innate immune system of the mammalian host with a range of potential effector functions against pathogens. These cells are rapidly recruited to sites of parasite infection. Counterintuitively, neutrophils favor the onset of parasite infections as we have described for sleeping sickness parasites (Trypanosoma brucei sp.) inoculated by the bites of tsetse flies. Indeed, selective neutrophil removal or genetic conditions resulting in lower neutrophil levels in the blood yield a higher level of resistance to trypanosome infection. Monocytes on the other hand are activated to differentiate into M1 macrophages that contribute to parasite control in the early stage of infection. The differential impact of neutrophils and macrophages suggests that specific inhibition of neutrophil functions could result in higher levels of resistance to infection. This project will compare the responses of neutrophils and monocytes to parasite presence by capturing their kinase activity fingerprints. Kinase targets in cell type specific and common responsive pathways will be identified. Kinase inhibitors from commercially available or proprietary collections will be used to selectively inhibit the parasite-induced responses and to evaluate the impact on parasite infection. Collectively, this project will forward our understanding of early trypanosome transmission and is directed at revealing novel transmission-blocking concepts and strategies.

Researcher(s)

Research team(s)

Project type(s)

  • Research Project

The role of parasite sanctuary sites and interaction with Kupffer cells in treatment failure of Visceral Leishmaniasis 01/10/2016 - 30/09/2020

Abstract

Visceral Leishmaniasis (VL) or Kala-Azar is a neglected tropical disease caused by Leishmania parasites that are able to survive inside macrophages. Miltefosine (MIL) is an oral drug used to treat VL patients but is increasingly failing to permanently clear parasites from the patient. Parasites from these relapse patients do not seem to display an increased resistance to the drug but are able to modify the immune system to promote survival inside macrophages even in conditions where the drug is administered. The impact of drug treatment on parasite survival will be evaluated in various tissues using molecular and imaging technologies in rodent models of VL following a natural parasite transmission. Recently, two syngeneic strains of L. infantum were selected with different levels of sensitivity to MIL-treatment in vivo. The resistant strain (and its sensitive counterpart) was made bioluminescent by introduction of the luciferase enzyme (PpyRE9). The use of bioluminescence imaging (BLI) allows the non-invasive evaluation of the parasite burden and distribution in various tissues and allows assessing the impact of MIL-treatment in vivo. The transgenic parasites will additionally be provided with a fluorescent marker (DsRed or TagGFP2) for detecting parasites by flow cytometry. This project aims to gain insights into the multifactorial causes of MIL-therapy failure and will focus specifically on the impact of the activation state of Kupffer cells (KC) and the recruitment of neutrophils. Infection with the two transgenic parasite lines will be followed by in vivo imaging in (i) KC-reporter (Clec4f-YFP DTR) mice in which KCs can be detected and enriched through their YFP signal and (ii) Genista mice in which a recessive mutation is responsible for a neutropenic condition with absence of mature neutrophils. This approach will allow to gain insights into the cell-based immunological basis of treatment failure. By transcriptional studies, this study will also allow us to identify the involved immunological pathways and potentially allow the design of host-directed therapies to reduce the risk of relapse. The multidisciplinary approach will lead to new insights into the complex interactions between the parasite, the host and the drug and will allow the formulation of recommendations for treatment against VL.

Researcher(s)

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  • Research Project

Identifying factors involved in miltefosine or amphotericin B treatment failure in visceral leishmaniasis. 01/10/2016 - 30/09/2019

Abstract

Amphotericin B (AmB) is currently implemented as first-line treatment for visceral leishmaniasis (VL) in large parts of the world, while the use of miltefosine (MIL) is endorsed as second option, either in mono- or in combination therapy. However, a cumulative number of treatment failures is being reported, requiring the need for repeated treatments that will facilitate emergence of resistance. As isolates from clinical relapse patients generally still demonstrate a 'drug susceptible' phenotype, factors other than intrinsic drug resistance may likely influence treatment outcome. For MIL, increased infectivity and metacyclogenesis potential of the infecting parasites has been suggested, while preliminary observations from our laboratory indicate similarities for AmB. Treatment failure has also been linked to a decreased drug exposure in particular parasite niches, such as in liver granulomas precluding sterile cure upon drug exposure. In this project, the complex interplay between the parasite's (epi-)phenotype, the drug and the host's immune system will be explored using syngeneic VL strains derived from a cure, relapse and resistant background. More in particular, virulence will be compared in the sand fly vector and in in vitro and in vivo laboratory models. The impact of the development of granulomas upon infection with the different strains will be compared in relation to the in vitro and in vivo drug efficacy and relapse potential.

Researcher(s)

Research team(s)

Project type(s)

  • Research Project

The role of parasite sanctuary sites and interaction with Kupffer cells in treatment failure of Visceral Leishmaniasis. 01/10/2016 - 30/09/2018

Abstract

Visceral Leishmaniasis (VL) or Kala-Azar is a neglected tropical disease caused by Leishmania parasites that are able to survive inside macrophages. Miltefosine is an oral drug used to treat VL patients but is increasingly failing to permanently clear parasites from the patient. Parasites from these relapse patients do not seem to display an increased resistance to the drug but are able to modify the immune system to promote survival inside macrophages even in conditions where the drug is administered. The impact of drug treatment on parasite survival will be evaluated in various tissues using molecular and imaging technologies in rodent models of VL following a natural parasite transmission. Combination of this information with the quantification of drug levels in these tissues, will allow to pinpoint in which tissues parasites are most likely to survive drug treatment. The expression of genes following infection and drug treatment will be analyzed inside infected liver macrophages (Kupffer cells, KCs) in order to understand how parasites from relapsed patients can survive inside host cells. Using transgenic mouse models, this research will allow to evaluate the impact of KCs and KC gene expression on infection and treatment outcome. Collectively, the proposed multidisciplinary approach will improve our understanding of the complex interactions between the parasite, its host and the drug and will allow the formulation of recommendations for improved treatment interventions.

Researcher(s)

Research team(s)

Project type(s)

  • Research Project

Study of miltefosine resistance mechanisms and dynamics through experimental selection of miltefosine-resistant Leishmania amastigotes. 01/10/2016 - 30/09/2018

Abstract

Our research focuses on resistance against the only oral drug miltefosine and will provide novel data to the field. Our results will not only be important to the parasitology field, but also to clinicians and public health professionals, supporting clinical decisions on future treatment policies, adequate diagnostic approaches and epidemiological resistance monitoring.

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  • Research Project

Mechanisms and dynamics of miltefosine resistance in leishmania donovani and l. Infantum laboratory strains and clinical field isolates. 01/01/2016 - 31/12/2019

Abstract

Visceral Leishmaniasis (VL) is the most deadly disease outcome of various forms of leishmaniasis and is caused by either L. donovani or L. infantum. First-line treatment still mainly relies on pentavalent antimonials, but drug resistance in both species is increasingly posing a threat to disease control. Miltefosine (MIL) has recently become available as first-line back-up drug, however, increased rates of treatment failure and relapses are now being reported in disease endemic areas, suggesting the emergence of drug resistance. To date, no optimal laboratory model exists to study the full impact of MIL resistance development as no resistant field strains could yet be identified in the laboratory. Mechanisms of drug resistance are most often studied in in vitro settings in which the parasite (generally promastigote stage) is directly exposed to a particular drug. At the University of Antwerp, the Laboratory for Microbiology, Parasitology and Hygiene (LMPH) developed a new in vitro assay on intracellular amastigotes to induce drug resistance while aspects of host-parasite interactions such as virulence (infectivity and fitness) and disease associated pathology are studied in laboratory rodent models. Both clinical field isolates and well-established laboratory parasite strains are used to assess dynamics and mechanism(s) of MIL resistance development, in parallel to in vivo virulence development and assessment of treatment relapse.

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  • Research Project

Primary and secondary in vitro evaluation of compounds against visceral leishmaniasis, human African trypanosomiasis and Chagas disease. 01/11/2015 - 31/12/2021

Abstract

This DnDi funded project relates to the preclinical evaluation of lead compounds with anti-parasitic activity for treatment of Leishmaniasis, Chagas disease and African trypanosomiasis. Compounds are also evaluated for cytotoxicity.

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  • Research Project

Characterisation of a novel Respiratory Syncytial Virus (RSV) immune evasion mechanism and evaluation of the impact for development of novel vaccines and prophylactic and/or therapeutic antibodies 01/10/2015 - 30/09/2019

Abstract

Respiratory Syncytial Virus (RSV) is the leading cause of severe lower respiratory disease in young children and is the second most important viral cause of respiratory disease in adulthood, after influenza virus. Currently, no vaccines and no antivirals are available to control RSV infections. Recent advances in RSV research have shown that the F protein is a major target for development of novel therapy and prophylaxis. F-specific antibodies, such as Palivizumab, are available, but were shown not to be fully effective, since hospitalization rates are reduced only by 55%. In addition, vaccines may also not fully protect against infection. This is exemplified by the fact that even after natural infection(s) and induction of F-specific neutralizing antibodies, RSV is able to reinfect. Since re-infection occurs without considerable antigenic change, there must be a different immune evasive mechanism than that influenza A virus reinfections, which is dependent on antigenic drift/shift. Our understanding of RSV F protein functionality, besides its role in fusion, is however insufficient to explain the immune evasive mechanisms involved. Currently there is a great risk that newly developed monoclonal antibodies and vaccines will suffer from constrained effectiveness. Very recently, preliminary studies in our research group have shown that upon binding of RSV-specific antibodies to RSV F protein expressed on the surface of infected cells, internalization occurs of RSV protein-antibody complexes. As a result, infected cells will most likely no longer be efficiently detected and eliminated by antibody-based immunity. In addition, a reduction in the expression of RSV proteins on the surface of infected cells may interfere with the immunogenicity and hamper the induction of strong immune responses. This novel finding may have profound effects on (1) our understanding of RSV pathogenesis and the occurrence of frequent RSV reinfections and (2) the development of new RSV vaccines and monoclonal antibodies. It is therefore the aim of this project to fully characterize this endocytosis process up to the molecular level, both in vitro and in vivo. We will (A) characterize the endocytic process and the consequences for RSV immune evasion, (B) identify amino acids of the F protein involved and create F proteins that show no internalization, (C) generate recombinant viruses with mutant F proteins lacking endocytic properties and (D) evaluate the recombinant viruses in vivo.

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  • Research Project

Medicinal Chemistry-Drug Discovery (ADDN). 01/01/2015 - 31/12/2020

Abstract

This project represents a research contract awarded by the University of Antwerp. The supervisor provides the Antwerp University research mentioned in the title of the project under the conditions stipulated by the university.

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  • Research Project

INFLA-MED - Fundamental research in the pathophysiological processes of inflammatory diseases. 01/01/2015 - 31/12/2019

Abstract

The Infla-Med consortium performs fundamental research on the pathophysiological processes of inflammatory diseases (cardiovascular, gastrointestinal, renal and infectious disease) by using a multidisciplinary approach (pathophysiology, pharmacology, biochemistry and medicinal chemistry). The consortium is embedded within the research priorities 'Drug Research' and 'Infectious Diseases' of the University of Antwerp. Recently, the University of Antwerp assigned the Infla-Med consortium as Research Consortium of Excellence.

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  • Research Project

Optimization of novel lead compounds for the treatment of African trypanosomiasis using innovative medicinal chemistry and formulation. 01/01/2015 - 31/12/2018

Abstract

The main objective of this research project is the lead optimization of the identified triazine series using medicinal chemistry and formulation technologies to increase the in vivo activity against T. brucei by combining enhanced solubility and metabolic stability with enhanced drug delivery.

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  • Research Project

Appui scientifique pour la realization du project interdisciplinaire/interuniversitaire en santé maternelle à Unikin et à Unilub 01/12/2014 - 30/11/2018

Abstract

This project represents a formal research agreement between UA and on the other hand VLIR. UA provides VLIR research results mentioned in the title of the project under the conditions as stipulated in this contract.

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    • Research Project

    Study of miltefosine resistance mechanisms and dynamics through experimental selection of miltefosine-resistant Leishmania amastigo. 01/10/2014 - 30/09/2016

    Abstract

    Our research focuses on resistance against the only oral drug miltefosine and will provide novel data to the field. Our results will not only be important to the parasitology field, but also to clinicians and public health professionals, supporting clinical decisions on future treatment policies, adequate diagnostic approaches and epidemiological resistance monitoring.

    Researcher(s)

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    • Research Project

    Equipment for high-speed refrigerated, preparative ultracentrifugation, automated gradient formation and fraction collection and analysis. 19/05/2014 - 31/12/2018

    Abstract

    This project represents a formal research agreement between UA and on the other hand the Hercules Foundation. UA provides the Hercules Foundation research results mentioned in the title of the project under the conditions as stipulated in this contract.

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    • Research Project

    Parasite-specific cyclic nucleotide phosphodiesterase inhibitors to target Neglected Parasitic Diseases (PDE4NPD). 01/03/2014 - 28/02/2018

    Abstract

    This project aims to unite global efforts to target the highly druggable class of enzymes called cyclic nucleotide phosphodiesterases (PDEs) in the fight for neglected parasitic diseases (NPD). It will establish a drug discovery platform, PDE4NPD, that combines phenotypic screening with efficient target-centric drug discovery, including target validation, various strategies for compound screening, PDE hit and lead optimization, safety and toxicology assessments and evaluation of anti-parasitic activity.

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    • Research Project

    Exploration of the biodiversity of Brazil to identify and evaluate novel bioactive compounds and extracts against infectious tropical diseases. 01/02/2014 - 31/01/2016

    Abstract

    This project represents a research agreement between UA and CAPES (Brasil). UA provides CAPES research results mentioned in the title of the project under the conditions as stipulated in this contract.

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    • Research Project

    Creation of a preclinical platform at the UA for testing novel therapeutic approaches against ocular surface diseases. 01/01/2014 - 31/12/2015

    Abstract

    Ocular Surface diseases (OSD) such as dry eye syndrome (DES) show an estimated prevalence between 15 and 29%. The only FDA approved and on subscription dry-eye treatment is cyclosporine 0.05% (Restasis®), but this formulation is not available in the EU. Novel therapies for OSD are therefore needed. The expertise within ADDN fosters a unique opportunity to set up a preclinical platform on OSD leading to an increased collaboration with industrial partners.

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    • Research Project

    Induction of miltefosine (MIL)-resistance on Leishmania amastigotes: study of the effect of resistance on MIL-internalisation, processing and parasitic fitness. 01/01/2013 - 31/12/2016

    Abstract

    Visceral leishmaniasis (VL) is caused by Leishmania donovani and L. infantum. Current drug therapies are associated with resistance, a high cost price, parenteral administration or serious side effects. Miltefosine (MIL) is the first oral drug against VL with a good therapeutic effect and ease of use and an acceptable safety profile. Recently, MIL was positioned as first-line therapy in India, Nepal and Bangladesh. However, MIL shows some characteristics that promote the emergence of resistance. The selection of MIL-resistant strains should be prevented and monitored, especially since there are no alternative drugs in clinical development. To proactively address the development of MIL-resistance, research on the resistance mechanisms and their cell biological and clinical implications is very important. This research project aims to obtain a standardized, clinically relevant laboratory model for the experimental induction of MIL-resistance. The MIL-resistant strains will be used to evaluate the effect of resistance on the MIL-uptake and parasite-cell interaction in Leishmania-infected macrophages. In addition, the fitness of the resistant strains will be assessed.

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    • Research Project

    Development of in vitro and in vivo laboratory models to analyse the dynamics of mono- and polymicrobial biofilm formation and treatment. 01/10/2012 - 30/09/2014

    Abstract

    Biofilm-related infections prove exceedingly difficult to treat because the organisms in a biofilm are protected from the circulating antimicrobials. Up till now, there have been relatively few studies investigating biofilm development in clinical isolates. Current in vitro methods for studying microbial adhesion and growth on biomaterial surfaces lack the influence of the host immune system, endorsing the specific need for animal models that allow temporal and spatial measurements based on non-invasive bio-imaging techniques using reporter strains. To improve our ability to prevent and/or treat biofilms, we need a better understanding of their formation and persistence. The specific goals of this research proposal are to i) understand the physiology of mono- and polymicrobial biofilms, with focus on staphylococci and Candida spp., isolated from indwelling devices from ICU patients and ii) implement in vitro and in vivo laboratory biofilm models that adequately reflect the real-life situation.

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    • Research Project

    Role of bacterial biofilms as a cause of therapeutic failure in intensive care units: in vitro and in vivo study of 'biofilms' virulence factors. 01/01/2012 - 31/12/2015

    Abstract

    This project represents a research agreement between the UA and on the onther hand IWT. UA provides IWT research results mentioned in the title of the project under the conditions as stipulated in this contract.

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    • Research Project

    Dynamics and mechanisms of paromomycin and miltefosine drug-resistance in the protozoan parasite Leishmania. 01/01/2012 - 31/12/2015

    Abstract

    The primary research aims of this project proposal are to unravel the dynamics and mechanisms of PMM and MIL resistance in L. donovani and L. infantum. To this end, our novel in vitro method for induction of drug resistance in amastigotes will enable to explore several aspects of PMM and MIL resistance prior to their routine use in the field. The deliverables of our study will contribute to the implementation of strategies/policies to avoid the appearance of drug resistance and assure the long-term efficacy of MIL and PMM.

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    Systemic mycoses: innovative laboratory models for basic, applied and epidemiological research. 01/01/2012 - 31/12/2013

    Abstract

    This project represents a research agreement between the UA and on the onther hand IWT. UA provides IWT research results mentioned in the title of the project under the conditions as stipulated in this contract.

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    A drug discovery with a particular focus on tropical protozoa (leishmaniasis, malaria, sleeping sickness and Chagas disease) and mycotic infections (yeasts, dermatophytes and fungi). 01/09/2011 - 31/12/2016

    Abstract

    This project represents a formal research agreement between UA and on the other hand DNDI. UA provides DNDI research results mentioned in the title of the project under the conditions as stipulated in this contract.

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    Topically applicable long-lasting glucocorticoid receptor agonists for the treatment of inflammatory skin diseases. 15/04/2011 - 14/04/2012

    Abstract

    This 'proof-of-concept' research is focussed on the development of innovative long-lasting and selective glucocorticoid receptor agonists for the topical treatment of skin inflammation diseases such as atopic dermatitis and psoriasis.

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    The role of bacterial biofilms as a major cause of therapeutic failure in intensive care units (ICU): an in vitro and in vivo study of 'biofilm' virulence factors. 01/01/2011 - 31/12/2014

    Abstract

    Bacterial isolates from intensive care unit patients will be collected from urinary and intravascular catheters and endotracheal tubes. The biofilm phenotype in relation to antibiotic treatment failure will be investigated using molecular biological, bio-imaging techniques and in vitro and in vivo biofilm models. Particular emphasis will be given to Escherichia coli for urinary tract infections (UTI), Pseudomonas aeruginosa for ventilation associated pneumonia (VAP) and Staphylococcus aureus for systemic infections related to venous catheters. The acquired library of fully typed strains will enable in depth study of putative virulence factors that contribute to biofilm formation and treatment failure.

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    Extended pharmacological study of the new antileishmania drug candidate oleylphosphocholine (OlPC) and exploration of other therapeutic areas to broaden its valorisation potential. 01/01/2011 - 01/11/2013

    Abstract

    This project represents a formal research agreement between UA and on the other hand Dafra. UA provides Dafra research results mentioned in the title of the project under the conditions as stipulated in this contract.

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    In vitro and in vivo study of mono- and polymicrobial biofilms as a major cause of therapeutic failure in intensive care units (ICU). 01/10/2010 - 30/09/2012

    Abstract

    Biofilm-related infections prove exceedingly difficult to treat because the organisms in a biofilm are protected from the circulating antimicrobials. Up till now, there have been relatively few studies investigating biofilm development in clinical isolates. Current in vitro methods for studying microbial adhesion and growth on biomaterial surfaces lack the influence of the host immune system, endorsing the specific need for animal models that allow temporal and spatial measurements based on non-invasive bio-imaging techniques using reporter strains. To improve our ability to prevent and/or treat biofilms, we need a better understanding of their formation and persistence. The specific goals of this research proposal are to i) understand the physiology of mono- and polymicrobial biofilms, with focus on staphylococci and Candida spp., isolated from indwelling devices from ICU patients and ii) implement in vitro and in vivo laboratory biofilm models that adequately reflect the real-life situation.

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    Repair of the flow cytometer at the Laboratory of Microbiology, Parasitology and Hygiene. 06/05/2010 - 31/12/2010

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    Systemic mycoses: innovative laboratory models for basic, applied and epidemiological research. 01/01/2010 - 31/12/2011

    Abstract

    This project represents a research agreement between the UA and on the onther hand IWT. UA provides IWT research results mentioned in the title of the project under the conditions as stipulated in this contract.

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    SSG resistance in Leishmania (Leishmania) donovani: relationship with fitness of the parasite and influence on other treatments. 01/01/2010 - 31/12/2011

    Abstract

    This project represents a research agreement between the UA and on the onther hand IWT. UA provides IWT research results mentioned in the title of the project under the conditions as stipulated in this contract.

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    Long-term monitoring for drug resistance of visceral leishmaniasis caused by Leishmania infantum in HIV patients. 01/01/2010 - 31/12/2010

    Abstract

    Determination of drug susceptibility of Leishmania strains isolated from HIV co-infected patients using a combined approach of biological in vitro susceptibility testing (LMPH) and molecular biology tools.

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    Study of the intestinal mucosal response and oxidative stress on the course of Giardia duodenalis infections. 01/10/2009 - 30/09/2011

    Abstract

    The project focuses on some fundamental biological characteristics of an infection with the parasitic protozoa Giardia intestinalis, more in particular: 1/ mucosal interactions between the parasite and the host using in vitro and in vivo models and 2/ intestinal pathogenetic factors (virulence, infalmmation, motility, e.a.) that will affect the clinical outcome of the infection.

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    Medicinal Chemistry-Drug Discovery (ADDN). 01/01/2009 - 31/12/2014

    Abstract

    This project represents a research contract awarded by the University of Antwerp. The supervisor provides the Antwerp University research mentioned in the title of the project under the conditions stipulated by the university.

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    Bacterial virulence as new target for protease inhibitors. 01/01/2009 - 31/12/2012

    Abstract

    The goal of this project is to gain insight in the role and applicability of protease (DPP4) inhibitors in bacterial infections. The proof-of-concept will be obtained in Porphyromonas gingivalis models with the following objectives and work packages: 1. Development of in vitro and in vivo virulence models for P. gingivalis. 2. Evaluation of enzyme inhibitors using purified recombinant P. gingivalis DPP4. 3. Evaluation of DPP/protease inhibitors in bacterial in vitro and in vivo models. 4. SAR and optimisation of the lead compounds. 5. Biochemical characterisation of lead compound-target enzyme interactions.

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    High performance LC-tandem mass spectrometry as necessary equipment for strategic research elucidation of chemical biomolecules and quantitative determination of medicines, metabolites and biomolecules in biological matrices. 19/12/2008 - 18/12/2013

    Abstract

    This project represents a research contract awarded by the University of Antwerp. The supervisor provides the Antwerp University research mentioned in the title of the project under the conditions stipulated by the university.

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    New tools for monitoring drug resistance and treatment response in visceral leishmaniasis in the Indian subcontinent. (KALADRUG-R). 01/11/2008 - 30/04/2013

    Abstract

    This EU-FP7 multi-disciplinary project, named KALADRUG-R, aims to develop, evaluate and disseminate new tools for evaluation of drug resistance in L. donovani as well as innovative methodologies for monitoring Kala-Azar treatment effectiveness under field conditions. The UA is specifically involved in basic research related to oxidative stress sensitivity to antimony-resistant strains and in applied research related to phenotypic evaluation of drug resistance in laboratory models. This involves in vitro growth end metacyclogenesis of promastigotes of field isolates and sensitivity evaluation at the level of intracellular amastigotes. The fitness profile of these field strains will be assessed in laboratory animal models.

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    The role of oxidative stress in infection dynamics and treatment of leishmaniasis. 01/10/2008 - 30/09/2011

    Abstract

    The specific objectives of this research proposal are: ¿ Optimisation and validation of EPR analysis for ex vivo quantification and identification of free radicals in macrophages. ¿ Determining the role of oxidative stress in the survival of the Leishmania parasite in the macrophage. ¿ Studying the link between oxidative stress and the action of current (antimonials) and new (PX-6518) antileishmanial compounds.

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    Protective gastro-intestinal effects of bovine milk fat globule membrane (MFGM) glycoproteins. 01/01/2008 - 31/12/2011

    Abstract

    The objective of the research is to obtain a series of well characterized fractions enriched in MFGM-glycoproteins with a high potential for anti-H.pylori action, due to their anti-adhesion and/or antimicrobial effects. In addition, these fractions will be checked for resistance towards gastro-intestinal digestion, and, in case of low digestibility, for possible effects on the composition and bioactivity of the microbiota in the large intestine.

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    SSG resistance in Leishmania (Leishmania) donovani: relationship with fitness of the parasite and influence on other treatments. 01/01/2008 - 31/12/2009

    Abstract

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    Study of the intestinal mucosal response and oxidative stress on the course of Giardia duodenalis infections. 01/10/2007 - 30/09/2009

    Abstract

    The project focuses on some fundamental biological characteristics of an infection with the parasitic protozoa Giardia intestinalis, more in particular: 1/ mucosal interactions between the parasite and the host using in vitro and in vivo models and 2/ intestinal pathogenetic factors (virulence, infalmmation, motility, e.a.) that will affect the clinical outcome of the infection.

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    Oxidative stress and inflammation: critical role in cardiovascular and infectious diseases. 01/07/2007 - 30/06/2011

    Abstract

    Oxidative stress is a pivotal factor in inflammatory processes, but research is hampered by the difficulties to detect free radicals, i.e. reactive oxygen species (ROS) and nitric oxide (NO¿). Objectives of this project include: 1/ validation of methods for in vitro quantification of ROS and NO¿ using electron paramagnetic resonance (EPR); 2/ visualisation of their cellular origin using modern microscopic imaging and 3/ application of these novel platforms to study ROS in inflammatory processes with focus on macrophage function, intracellular infections, atherosclerosis and heart failure.

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      Suitability of the novel antileishmania lead compound PX-6518 as a drug candidate against New-World leishmaniases. 01/06/2007 - 31/05/2008

      Abstract

      The project contains field research in the context of the ongoing activity profiling of PX-6518 against cutaneous Leishmania species. Primary objectives are to obtain insight and experience in New-World leishmaniasis and to transfer validated in vitro laboratory Leishmania models between the North and the South partner. The action of the new antileishmania lead compound PX-6518 against recently collected Peruvian field CL-strains will be further studied within a collaboration between the UA-LMPH and the University at Lima, Peru.

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      In vitro susceptibility of Leishmania (Leishmania) donovani to antimonials and the effector mechanisms of the macrophage: what is the best marker for treatment failure? 01/01/2007 - 31/12/2007

      Abstract

      Visceral leishmaniasis (VL) is a tropical parasitic disease due to infection with Leishmania (Leishmania) infantum or Leishmania (Leishmania) donovani that primarily affects the liver, the spleen and the bone marrow. Worldwide, antimonials are the first line treatment of VL, but in some regions, as North-East India and the bordering regions in Nepal, treatment failure due to the parasite has emerged and seems to be spreading. This project will contribute to a better understanding of (i) the interaction between Leishmania and its host cell, the macrophage, (ii) the action mechanism of antimonials, (iii) in vitro resistance of Leishmania to antimonials and (iv) the in vivo treatment failure. Eventually, we hope to identify a molecular marker of treatment failure of antimonials to be able to efficiently follow up the emergence and further spreading of parasites causing treatment failure, what is of the greatest importance for setting up and evaluating control measures.

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      Medicinal Chemistry-Drug Discovery (ADDN). 01/11/2006 - 31/12/2008

      Abstract

      This project represents a research contract awarded by the University of Antwerp. The supervisor provides the Antwerp University research mentioned in the title of the project under the conditions stipulated by the university.

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      Study of the intestinal mucosal response and oxidative stress on the course of Giardia duodenalis infections in laboratory animal models. 01/10/2006 - 30/09/2007

      Abstract

      A new research initiative will study the micro-aerophilic intestinal protozoa Giardia intestinalis. This pathogen has developed anti-oxidative defense mechanisms to withstand the oxygen tension in tissues and organs, e.g. via oxidation of cellular thiols, superoxide-dismutase and possibly other mechanisms. The importance of these mechanisms is illustrated by the fact that current therapeutics (nitro-compounds) exert their action via selective increase of oxidative stress. The research plan involves the following steps: 1. development/optimization of in vitro culture method for trophozoites 2. establishment of conditions for induction of cyst formation, 3. development of a suitable laboratory animal model, 4. influence of oxidative stress on the in vitro and in vivo survival by in situ quantification of oxidative/antioxidative phenomena 5. evaluation of new molecules in the in vitro and in vivo models 6. evaluation of disinfectants for inactivation of cysts in drinking water 7. interaction of the parasite with intestinal lining (pathology, inflammation, e.a..)

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      Integrated evaluation of test compounds against Leishmania and Trypanosoma parasite species. 01/09/2006 - 31/10/2015

      Abstract

      For most infectious diseases, chemotherapeutics are still required for disease control as vaccines are generally lacking. In addition, drug resistance has become a critical issue, which endorses the need for continuous drug research. LMPH is actively involved in the identification of new synthetic and natural lead compounds, with a particular focus on the tropical protozoal diseases Leishmaniasis, sleeping sickness, Chagas disease and malaria. Validated in vitro and in vivo test systems and drug screening technologies have been developed. The Drugs for Neglected Diseases Initiative (DNDi) has access to compound libraries which have never been tested for the listed diseases. In this project, both groups have joined expertise and know-how to achieve a more productive drug discovery platform.

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      Molecular markers for epidemiological monitoring of drug resistance in visceral leishmaniasis. 01/01/2006 - 31/12/2009

      Abstract

      Treatment of the tropical disease leishmanisis is beconing more difficult be cause of the emergence of widespread resistance against the first-line drugs. Epidemiological studies on the prevalence and spread of drug-resistance forms a basis for the correct positioning of treatment strategies. This project will run a phenotyping of Leishmania donovani field strains and will develop molecular tools for the detection of natural SBV-resistance. More in particular, the following objectives are considered: 1. Identification of resistance markers that correlate best in natural SbV resistant field strains 2. Experimental verification of the role of the selected markers on the in vitro resistant phenotype 3. Evaluation of the developed molecular tools for SbV resistance in clinical samples of VL patients 4. Evaluation of the correlation between the presence fo R-markers and therapeutic failure after SbV treatment.

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      Mode-of-action, pharmacodynamics and toxicity of a triterpene saponin PX-6518, a potent new lead structure with selective antileishmania activity. 01/05/2005 - 30/04/2009

      Abstract

      PX-6518 is a triterpene saponin with a broad-spectrum antileishmania action. Its mode-of-action is still unknown and in vitro and in vivo research is planned to investigate 1/ compound-induced structural changes (histology, EM) of the different parasite stages, 2/ relation between selective accumulation into the phagolysosome and antileishmania activity and 3/ pharmacodynamics and toxicity in the visceral Leishmania hamster model (histopathology, serum biochemistry).

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      Drug research and discovery platform for tropical parasitic diseases within a public-private partnership. 01/12/2004 - 31/12/2011

      Abstract

      The University of Antwerp (UA) and the Institute of Tropical Medicine Antwerp (IMTA) together with the pharmaceutical industry partner Tibotec have agreed to collaborate in lead-finding and lead-exploration for tropical & neglected diseases, such as malaria, leishmaniasis, sleeping sickness and Chagas disease. Practically, a test battery for medium throughput in vitro drug evaluation will be set up on the basis of the joint technical know-how to accommodate, among others, for the current screening needs by WHO-TDR. Compound (chemicals and natural products) acquisition through existing networks will continue and dedicated compound-handling logistics will be implemented. As a secondary objective, capacity will be created to assess `drug developability' through early pharmacological and pre-clinical profiling of selected `hits'. This project focuses on tropical diseases that remain of prime interest to WHO-TDR and offers realistic possibilities of identifying new leads.

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      • Research Project