Research team

Laboratory for Microbiology, Parasitology and Hygiene (LMPH)

Expertise

In vitro and in vivo biofilm assays, Integrated antimicrobial (bacteria, fungi, yeasts and parasites) screening and profiling of pure compounds and extracts, targeting redox homeostasis in mycobacteria

Biology and ecology of bacterial and fungal biofilms in humans. 01/01/2021 - 31/12/2025

Abstract

This is a fundamental research project financed by the Research Foundation - Flanders (FWO). The aim of this research community is to better understand the formation and the structure of bacterial and fungal biofilms in humans. This could lead to a more efficient treatment of biofilm-related infections.

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Persistence in Streptococcus pneumoniae infections: elucidation of the importance of persister cells in chronic and recurrent infections 01/11/2020 - 31/10/2022

Abstract

Streptococcus pneumoniae is an important human pathogen, as it is one of the most common causes of community-acquired pneumonia and otitis media. Several issues arise when battling these infections. First, replacement of vaccine-serotypes by new ones has been observed. Second, antibiotic resistance is an emerging problem. Also, antibiotic persistence is considered an important, yet underexposed phenomenon. Persister cells are a subpopulation of cells that are tolerant to lethal concentrations of antibiotics and are involved in a variety of chronic and recurrent infections. However, little to nothing is known about persister formation in S. pneumoniae. This project aims to fill this gap in knowledge. As in vitro autolysis hampers the prolonged monitoring of cultures, a variety of strategies – including the generation of mutant strains – will be applied to overcome this issue. Using heritability assays and gene sequencing to exclude arising of antimicrobial resistance, the presence of persisters will be confirmed. Furthermore, an in vivo model for persister studies will be optimized to confirm the clinical relevance of in vitro results. Lastly, the propensity to form persisters, the antimicrobial susceptibility profile, the strain origin and the in vivo virulence of a set of 50 clinical isolates will be evaluated. Collectively, this project will significantly progress our understanding of importance of persisters in the pathology of S. pneumoniae infections.

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In vivo evaluation of biofilm-related pneumonia. 01/10/2020 - 30/09/2021

Abstract

Biofilm formation during lung infection is related to persistent infection. This is a characteristic of chronic diseases such as Cystic Fibrosis (CF). Moreover, biofilm formation in endotracheal tubes (ETT) is related to the onset of Ventilator-Associated Pneumonia (VAP). Failure in treatment is associated with high morbidity and mortality. In addition to increased resistance, antibiotic therapy failure can also result from regrowth of a subset of cells in bacterial populations that are called persisters. When challenged with a lethal dose of antibiotics, this small fraction of transiently antibiotic tolerant cells survives to give origin to a new population and they are then related to the chronic nature of pneumonia. Therefore, new ideas to prevent and treat biofilm-related lung infections are required. New antibacterial targets and incorporation of antibacterial compounds in 3D printed catheters are being investigated. A chronic P. aeruginosa lung infection model, based on intratracheal infection of bacteria encapsulated in seaweed alginate beads, was optimized to characterize persistence in collaboration with KULeuven. This animal model mimics cystic fibrosis (CF) and several low and high persister laboratory strains are currently being studied in vivo to validate the infection dose and the treatment scheme for persistence studies. Natural isolates from other clinical settings, including animal and environmental origin, will also be tested. The VAP model is in the framework of an H2020 ETN project called PRINT-AID. The aim of this project is to proof the value of developing a new generation of 3D-printed personalized medical devices with antimicrobial functionalities. Screening of new drug leads, in vitro testing in dynamic biofilm systems and cell models and improvement of the manufacturing process of 3D printed and coated catheters are currently being performed by collaborators. UAntwerp will be responsible for the development of a VAP mouse model in which the 3D produced tubes will be inserted in the main bronchus intratracheally. The tubes will be inoculated with biofilm-forming S. aureus and with this model we aim to evaluate the inhibition of bacterial adherence to the tubes in vivo and the anti-infective efficacy of the tubes by assessing the bacterial burden in the lungs.

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Springboard for excellence in advanced development of antibacterials (SPRINGBOARD). 01/09/2020 - 31/08/2023

Abstract

The main goal of SPRINGBOARD project is to strengthen research potential of the Latvian Institute of Organic Synthesis (LIOS) through establishing long-lasting and sustainable collaboration network with the leading European research institutions – University of Antwerp, University of Copenhagen, University of Florence and University of Helsinki – in the area of advanced discovery and design of novel antibacterial drugs.

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3D printing of drug loaded medical devices for personalized medicine. 01/05/2020 - 30/04/2022

Abstract

Additive manufacturing (AM) technologies have been extensively used in many fields and applications. Personalized medicine is one of the most promising fields that could benefit from such technologies. The Food and drug administration (FDA) approved in 2016 the first drug loaded device produced via AM introduced by Aprecia Pharmaceuticals. Fused filament fabrication (FFF) is one of the AM technologies that rely on the extrusion of a melted polymeric material through a nozzle. The consecutive movement in three-dimensional space while extruding material results in producing objects with high geometrical complexity. Such produced objects were not possible to build through conventional manufacturing technologies. This technology specifically has high potential in the pharmaceutical sector as it relies on a well-known technology used for producing drug loaded polymeric formulations, called hot melt extrusion (HME). In this technology a carrier polymer is mixed with a known active pharmaceutical ingredient (API) using a screw extrusion system and then hot extruded through a die for further processing. This project is a continuation of the PrintAID ITN-project. It aims at utilizing 3D-printing technologies for printing anti-infective medical devices. These devices should have the ability to prevent biofilm-related infections. Selected antibacterial agents will be analyzed for their thermal stability as the 3D printing process uses heat for processing. On the other hand, thermoplastic polymers will be investigated for their mechanical, rheological and thermal properties and the best ones will be selected as carrier for the antibacterial agents. The fused filament fabrication 3D printing technology will be modified and used to produce medical devices using the selected formulation. The modification will focus on reconfiguring the extrusion system to convert it from a conventional filament extruder to a pellet extruder, thereby providing more versatility in material selection. These devices will be analyzed in terms of mechanical integrity and formulation stability. in vitro and in vivo samples will be produced to study the release profile and the killing efficacy of the selected APIs. The intended goal is to produce proof-of-concept devices to tackle bacterial-associated infections on indwelling devices such as endotracheal tubes.

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The exploration of novel rapid technologies and alternatives to conventional microbiological test approaches (μRATE). 01/04/2020 - 31/03/2023

Abstract

The project entitled "The Exploration of novel rapid technologies and alternatives to conventional microbiological test approaches" will explore new methodologies to replace conventional microbial quality testing methodologies.

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iMI-project - support - RespiriTB and RaspiriNTM 01/01/2020 - 31/12/2023

Abstract

Non-tuberculous mycobacteria, such as Mycobacterium avium complex (MAC) and Mycobacterium abscessus, cause lung diseases resembling TB, mainly in immune-compromised patients or patients suffering from other lung diseases (e.g. cystic fibrosis). The incidence and prevalence of lung diseases caused by NTM are increasing worldwide. Importantly, in the US and Japan, as well as in other areas of the world where TB has declined, NTM disease is already at least three times more prevalent than TB. Treatment of NTM diseases relies on antibiotic combinations, however the drugs active against NTM are rather few and mainly different than those active against TB. These NTM treatments for the most common species (MAC and M. abscessus) are much less active than the current anti-TB regimen is for TB treatment. It is often necessary to administer antibiotic combinations for at least 12-24 months. The long and complex drug regimen that is currently recommended as a treatment against NTM-caused diseases carries the risk of inducing resistance in NTM. Several studies have already shown the existence and emergence of multidrug resistant NTM. The overall objective of RESPIRI-NTM is to find new drug candidates as potential components of a new, more efficient combination drug regimen against NTM that is less prone to resistance and allows shortening of treatment duration for NTM and multidrug-resistant NTM. Such a drug combination will synergistically target the energy metabolism of NTM or complementary targets. To achieve this, we will advance recently discovered inhibitors of the mycobacterial respiratory pathway. In addition, we will perform a novel, phenotypic screen in order to identify novel targets in NTM. Finally, we will also target host-factors that are essential for the intracellular survival of NTM. Together, we present a comprehensive plan to find novel strategies to combat non-tuberculous mycobacteria, shorten treatment time and reduce chances of drug resistance.

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A platform to functionally assess clinically relevant respiratory parameters in small animal models for infectious and non-infectious pulmonary research. 01/01/2020 - 31/12/2021

Abstract

This application relates to the purchase of new basic infrastructure, more specific a FlexiVent system from Emka Technologies. FlexiVent is a platform for standard respiratory research that can be used across many pulmonary applications and which has major advantages compared to the classical, non-invasive, unrestrained plethysmography because it is accurate, reproducible and proven. FlexiVent is much more capable of detecting pulmonary abnormalities via changes in functional residual capacity, total lung capacity, vital capacity, and compliance of the respiratory system. Furthermore, analysis of pulmonary functions via FlexiVent allows distinction between respiratory diseases in mice by clinically relevant variables and is therefore generally accepted as the standard in the functional evaluation of infectious and non-infectious pathological, respiratory disease models.

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Exploitation of key enzymes of the mycothiol biosynthesis to improve treatment of mycobacterium avium complex infections. 01/11/2019 - 30/10/2021

Abstract

Worldwide, pulmonary disease caused by members of the Mycobacterium avium complex (MAC) is increasing. Treatment of MAC lung disease requires a multidrug chemotherapy that takes up to 12 months and often leads to adverse drug effects, treatment failure, MAC reinfection and the emergence of drug resistance. New strategies need to be explored that can lead to more successful treatment of MAC infection. Mycothiol cysteine ligase (MshC) and the mycothione reductase (Mtr) are two key enzymes of the bacillary redox homeostasis and are unexploited drug targets. We hypothesize that these genes play an essential role for both the virulence and the stress tolerance within MAC and that targeting these genes would synergize with existing and emerging antimycobacterial therapeutics. In this project proposal we aim to investigate these hypotheses by the generation of a panel of recombinant MAC strains in order to study the impact of the target genes on the physiological growth, stress tolerance, cellular and in vivo virulence and synergy with existing and emerging MAC therapeutics. The findings can support future target-based drug development programs of potential Mtr and MshC inhibitors. In the long run, the findings within this research could lead to a safer, shorter and more cost-effective treatment of MAC infection.

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Progress new assets (one pre-new molecular entity and one first-time-in-human start) for tuberculosis that act synergistically with bedaquiline, cytochrome bc or cytochrome bd inhibitors (RespiriTB). 01/05/2019 - 30/04/2025

Abstract

Despite recent progress in biomedical research, Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is still the world's leading infectious disease killer worldwide. Treatment options are limited, and expensive, recommended medicines are not always available in many countries, and patients experience many adverse effects from the drugs. Thus, there is an acute need for the development of a novel combination regimen with an indication for effective, shorter, and safer treatment of all forms of TB. The overall objective of RESPIRI-TB is to find new drug candidates as potential components of a new, more efficient combination drug regimen against TB that is less prone to resistance and allows shortening of treatment duration for TB, and multidrug-resistant TB. Such a drug combination will synergistically target the energy metabolism of Mtb or complementary targets. To achieve this, we will advance recently discovered inhibitors of the Mtb respiratory pathway. In addition, we will target the Mtb specific molecular mechanism that reduces reactive oxygen species in the cell.

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Turning black into golden soldier fly larvae (Hermetia Illucens): added value creation by exploring its microbiota and metabolism (ETOBIOTA). 01/01/2019 - 31/12/2022

Abstract

Black Soldier Fly Larvae (BSFL) are larvae from the insect the black soldier fly. They are currently being reared on a global industrial scale as a feed ingredient. They can be reared on a wide range of side and waste streams from food industry and agriculture, being converters of these streams into valuable biomass. Given the struggle of our food system to sustainably meet the protein demands of the growing world population, BSFL rearing offers an innovative, bio-based alternative contributing to a circular economy. As insect production is a novel branch of livestock production, it is up to (academic) researchers to gather the same level of in-depth knowledge that is available for other farm animals on production safety and optimization. For example, the impact of the chemical and microbial composition of the feed on the zootechnical performance and on the microbial safety of BSFL is virtually unknown. Furthermore, preliminary research points towards high value applications for other industrial sectors, such as the pharma and waste treatment sector, that could generate more profit for the insect production sector. This project aims to generate more fundamental knowledge that could support the insect sector, legislation and the co-emerging food value chain to remove legislative and technical hurdles in rearing and valorisation. More specifically, we will explore the hardly investigated interaction between the BSFL, their substrate and their gut microbiota. Such interactions are expected to depend on the substrate and affect (i) the growth of the larvae, (ii) their microbial safety, and (iii) their chemical safety. The overall goal of this project is to define and characterize a set of microorganisms that can be used to manipulate the gut microbiota of BSFL in order to boost its performance in each of the three aforementioned domains and increase their economic value.

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Natural products and pharmaceutical services to improve the patient quality of life in Eastern Cuban Hospital's. 01/01/2019 - 31/12/2022

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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Exploring the anti-inflammatory potential of Rothia mucilaginosa in chronic lung diseases. 01/01/2019 - 31/12/2022

Abstract

In this project, we will confirm the anti-inflammatory effects of Rothia mucilaginosa in complex and physiologically relevant in vitro models of CF and COPD lung inflammation, as well as in in vivo mouse models. The anti-inflammatory compound(s) produced by this bacterium will be identified and the mode of action unveiled.

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Development of a comprehensive platform for targeting redox homeostasis in Mycobacterium tuberculosis. 01/01/2019 - 31/12/2022

Abstract

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), remains a major public health hazard throughout the world and was responsible for more than 1.7 million deaths in 2016.The prevalence of drug resistance in Mtb calls for the legitimization of new and highly specific drug targets, focusing on unique pathways.The project encompasses a multidisciplinary approach to disturb the redox homeostasis in Mtb, in an effort to uncover new drug leads for fighting this deadly infection.

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Research on a new concept to improve the treatment of recurrent Candida albicans infections 01/09/2018 - 31/08/2021

Abstract

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

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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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Integrated Training in Dry Eye Disease Drug Development (IT-DED3). 01/01/2018 - 31/12/2021

Abstract

The European network for Integrated Training in Dry Eye Disease Drug Development (IT-DED3) aims to deliver multidisciplinary and entrepreneurial researchers trained to develop new therapies for patients suffering from dry eye diseases (DED). DED is a chronic, multifactorial disease of the ocular surface and is a major and increasing healthcare problem due to its high prevalence and economic burden because of the ageing population and frequent computer/tablet/smartphone usage. New DED drug development and translation from "bench to bedside" is urgently needed and therefore IT-DED3 integrates worldclass expertise in medicinal chemistry, process chemistry, ocular drug delivery and formulation, DED models, imaging, biomarker research and clinical ophthalmology. The scientific novelty is manifold, including new drug targets and compound classes, innovative formulation strategies for ocular drug delivery, and novel optical and molecular biomarkers identified by new imaging techniques and genomic-based systematic screening of a database of DED patients. The consortium of 7 beneficiaries and 10 partners (in total 7 from the non-academic sector) from 8 different European countries will select 12 early stage researchers (ESRs). Each ESR will perform high level scientific research in this stimulating multidisciplinary, international and intersectoral environment. Besides the scientific skills, the Personal Career Development Plan (PCDP) of each ESR will include transferable skills such as data management, project and time management, communication and dissemination, IP and valorisation. Both the research and training programme of IT-DED3 will deliver researchers with an enhanced career perspective and employability, who know how to use their entrepreneurial skills to move drug development projects in DED and other fields to the next technology readiness level.

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Installing a center of excellence in the Central-Eastern region of Cuba to enhance production and research on bioactive plants. 01/01/2017 - 31/12/2021

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. The aim of the project is to set-up a center of scientific excellence in the Central-Eastern region of Cuba for traditionally used bioactive plants and their metabolites.

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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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RNA biomarkers discovery for ultra-fast drug synergy and susceptibility testing in the mycobacterium avium complex. 01/01/2020 - 31/10/2020

Abstract

Pulmonary infections caused by the Mycobacterium avium–intracellulare complex (MAC) are slow and progressive, and increasingly prevalent in developed countries. They can be cured, but their treatment consists of a 12 months multidrug regimen. A key issue standing in the way of designing more effective treatment regimens is the lack of a diagnostic tool for drug susceptibility testing (DST) in MAC. Current methods are slow (3-5 weeks), poorly reproducible and their results are difficult to interpret by clinicians. In this project, we will design a novel DST for MAC infections. It is based on the idea that a susceptible bug will feel stress under attack of an antibiotic, and a resistant one will not. The test is based on multiplex measurements of relative quantities of antibiotic-specific RNA biomarkers after short exposure to the drug. This test is unlike any test on the market. The project start fundamental, with transcriptional analyses of MAC cells under antibiotic stress. We will identify drug-specific sets of stress genes, and convert these into a Luminex-based format for multiplex quantification. The test parameters will be optimized using contemporary clinical strains, in collaboration with the National Reference Centre for Mycobacteria. Finally, we will apply our platform to identify synergetic interaction between novel and old compounds to derive optimal drug combinations with the strongest possible effect on clinical MAC strains.

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Nanobody-assisted targeting of sialoadhesin-positive macrophages to improve the treatment of tuberculosis. 01/10/2017 - 30/09/2020

Abstract

Treatment of tuberculosis is severely complicated by the adaptations of its etiological agent, Mycobacterium tuberculosis, allowing survival and replication within the host phagocytes. A better understanding of the host-pathogen interaction and the development of novel treatment strategies are thus critical. We strongly believe in a promising strategy involving the receptor-mediated delivery of therapeutics via the endocytic Sialoadhesin (Sn) receptor present on the surface of phagocytes.

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Miconazole feasibility study 01/05/2017 - 31/12/2017

Abstract

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

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A miconazole potentator combination therapy as novel treatment for recurrent vulvovaginal candidiasis: a kick-start of a novel mycology business case. 01/03/2017 - 01/12/2017

Abstract

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

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Multidisciplinary European training network for development of personalized anti-infective medical devices combining printing technologies and antimicrobial functionality (PRINT-AID). 01/01/2017 - 31/12/2020

Abstract

According to ECDC, over 4 million healthcare-associated infections in the EU cause 37,000 deaths and cost EUR 7 billion/year. Half of them are related to medical devices (i.e., catheters, implants) and 80% of these are related to bacterial biofilms. A recent EC report highlighted the medical device sector's role in driving EU economic growth, employing 500k people in 25k companies (80% are SMEs) with annual sales of EUR 85 billion. The strategy to prevent medical device-infections is alteration of the device's surface with antimicrobials. However, current antimicrobial surfaces don't control bacterial growth in tissue surrounding implants, and only Sterilex® has received regulatory approval in the US as anti-biofilm agent. Participants in this proposal have earlier demonstrated a dramatic in vitro inhibition of biofilm formation by 3D-printing surfaces with antibiotics incorporated into the carrier polymers. This discovery opens new possibilities for printed medical devices that better resist biofilms. Our objective is to setup a new European education platform to guide and inspire young researchers in the intersectoral exploration of innovative routes to counteract microbial biofilms by fabricating anti-infective, tailored, 3D-printed medical devices. Current opportunities for young researchers to receive an structured, inter-sectoral and up-to-date education on personalized medicine and medical devices are marginal, and to our knowledge PRINT-AID is the first ETN set up for this purpose. State-of-the-art printing technologies will be combined with in vitro and in vivo biofilm models and novel tools for data integration/standardization. Doctoral training will be performed within a high-quality network of 12 participants (5 industrial) from the EU and US. It will include online and face-to-face courses taught by researchers with academic and industrial expertise in biofilms, 3D-printing research, antimicrobials, material science, and drug development.

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In vivo multidrug-tolerant persister cells and their evolution in the face of antibiotic treatment: genetic and physiological adaptation mechanisms. 01/01/2017 - 31/12/2020

Abstract

Antibiotics have revolutionized medical practice against life-threatening infectious diseases. However, the evolution of antibiotic resistance currently poses a major threat to health-care, leading to worldwide increased morbidity and mortality. In addition to resistance, it is becoming clear that antibiotic therapy failure in many bacteria also results from a subset of cells that have switched to an antibiotic-tolerant "persister" state. Indeed, the survival of an antibiotic-sensitive bacterial population challenged with the lethal activity of antibiotics critically depends on the presence of this small fraction of non-growing, transiently antibiotic-tolerant cells. A recent study demonstrates that Escherichia coli persister levels can be very quickly tuned to the frequency of previous antibiotic encounters by genetic adaptation, leading to extreme levels of multidrug tolerant persisters when applying antibiotics daily. A similar rapid evolution of persistence was demonstrated in many important bacterial pathogens including urinary pathogenic E. coli and Burkholderia. Together, these results indicate that bacteria can genetically store information of past antibiotic treatments. We hypothesize that a similar evolutionary process may occur in vivo, thereby impeding successful clearance of the bacteria from the host. We will test this hypothesis by performing in vivo evolution experiments using urinary tract and lung infection models in mice.

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Biological evaluation of 1,3-diaryltriazenes and their mechanism of action on Mycobacterium tuberculosis. 01/02/2016 - 05/01/2020

Abstract

A strong anti-mycobacterial activity was found for a group of symmetrically substituted 1,3-diaryltriazenes. The compounds did not show genotoxicity and mutagenicity and the anti-mycobacterial activity was dependent on the substitution pattern. In this project we want to investigate (i) how the current lead compound can be optimized, (ii) if the compounds fulfill the WHO criteria and (iii) what the mechanism of action is of the 1,3-diaryltriazenes.

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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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Elucidating the mechanism of action of octahydrobenzo[j] phenanthridinediones as novel potent antimycobacterial compounds. 01/10/2014 - 30/09/2017

Abstract

(Mtb) are in high demand. In a past FWO project (G0020.10N) we synthesized and identified the class of octahydrobenzo[j]phenanthridinediones as promising antitubercular drug candidates. Ester analogs of the compound class showed a high degree of selectivity. For these compounds, we observed a sub-μM minimal inhibitory concentration against Mtb nearly 200 times lower than the 50% cytotoxic concentration against eukaryotic cells. However, the mechanism of action and the basis of selectivity remain unknown. Therefore, the general objective of this project is to study the mechanism of action of the octahydrobenzo[j]phenanthridinediones. We hypothesize a selective inhibition of mycothione reductase, a unique redox pathway in Actinobacteria, as the action mechanism. To this end,(i) we will identify the proposed target through genomic analysis of spontaneous Mtb mutants.(ii) We will validate the identified target through enzymatic and cellular approaches. (iii) In addition, we will study the activity against metabolically inactive bacilli and the synergism with existing TB drugs using state of the art models. This study will contribute to the fundamental understanding of the mechanism of action of the compound class and will add to the common knowledge on mycobacterial mycothione reductase. In the long term, the gathered knowledge could add to the development of new antitubercular drugs.

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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.

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Pathogenetic role of endothelial nitric oxide synthase uncoupling in ischemia- and reperfusion injury of the lung. 01/10/2014 - 30/09/2016

Abstract

The objective of our research is to determine whether the process of eNOS uncoupling can also be demonstrated in lung tissue after ischemia and reperfusion injury (IRI). In the first part of the project, experimental techniques were developed in order to detect free radical production during IRI using electron paramagnetic resonance. A murine model of pulmonary IRI was also developed. We are currently working on the effect of eNOS itself, and eNOS uncoupling, on free radical generation during pulkmonary IRI. Our final aim is to develop therapeutic strategies to tackle pulmonary IRI in patients undergoing complex surgery such as cardiopulmonary bypass, lung transplantation and isolated lung perfusion.

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Modelling microbial growth during solid state fermentation 01/07/2014 - 31/12/2015

Abstract

Although good performance of solid state fermentation (SSF) on the lab scale, the industrial scale process has drawbacks, such as, poor heat transfer and difficult pH control. Bottleneck is the lack of information about the kinetics in SSF systems caused by the heterogeneous nature and complexity of the process. This project aims to model the kinetics of Monascus growth on rice based on experiments in a computer controlled solid state fermenter.

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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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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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Biopharmaceutical products from natural sources to biotechnological development. 01/04/2013 - 31/03/2019

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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Study of the role of membrane receptor signalisation in immune cell infection and regulation. 01/01/2013 - 31/12/2016

Abstract

This project aims to identify new mechanisms for the modulation of macrophages during activation of the immune system and during pathogen infections, using sialoadhesin, a macrophage-specific surface protein.

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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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Fighting infectious diseases with combination therapy: targeting sociomicrobiological processes to circumvent antimicrobial resistance. 01/01/2013 - 31/12/2016

Abstract

This project represents a research agreement between the UA and on the other 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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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.

Researcher(s)

Research team(s)

Ontogeny of CYPs and drug transporters in the gastrointestinal tract of zebrafish. 16/09/2012 - 15/07/2015

Abstract

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

Researcher(s)

Research team(s)

The role of oxidative stress tolerance in the antibiotic resistance of biofilms formed by Gram-negative bacteria. 01/01/2012 - 31/12/2015

Abstract

In this research project we will be investigating fundamental aspects related to the action of antibiotics against biofilms. In addition, in the long term our results could lead to the rational development of non-toxic agents that reduce the ability of biofilm cells to deal with ROS-related stress and could be used in combination with conventional bactericidal antibiotics.

Researcher(s)

Research team(s)

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.

Researcher(s)

Research team(s)

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.

Researcher(s)

Research team(s)

Biology and ecology of bacterial and fungal biofilms in humans. 01/01/2011 - 31/12/2020

Abstract

This is a fundamental research project financed by the Research Foundation - Flanders (FWO). The aim of this research community is to better understand the formation and the structure of bacterial and fungal biofilms in humans. This could lead to a more efficient treatment of biofilm-related infections.

Researcher(s)

Research team(s)

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.

Researcher(s)

Research team(s)

Applicability of dipeptidyl peptidase inhibitors as an anti-virulence therapy in Porphyromonas gingivalis infections. 01/01/2011 - 31/12/2014

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.

Researcher(s)

Research team(s)

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.

Researcher(s)

Research team(s)

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.

Researcher(s)

Research team(s)

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.

Researcher(s)

Research team(s)

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.

Researcher(s)

Research team(s)

Research on bacterial virulence inhibitors with predictive in vitro and in vivo models. 01/07/2009 - 31/12/2013

Abstract

The goal of this project is to gain insight in the role and applicability of virulence inhibitors in bacterial infections. The objectives are: 1. Development of an in vitro multi-species biofilm model with P.gingivalis. 2. Development of an in vitro virulence model for P. gingivalis-mediated collagen degradation. 3. Development of P.gingivalis animal model. 4. Evaluation of virulence inhibitors in bacterial in vitro and in vivo models.

Researcher(s)

Research team(s)

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.

Researcher(s)

Research team(s)

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.

Researcher(s)

Research team(s)

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.

Researcher(s)

Research team(s)

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.

Researcher(s)

Research team(s)

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..)

Researcher(s)

Research team(s)

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.

Researcher(s)

Research team(s)

Development and validation of a microtiter plate model for the evaluation of biocides against Staphylococcus aureus biofilms. 01/03/2006 - 31/12/2007

Abstract

A biofilm is defined as a microbially-derived sessile or adherent community embedded in a matrix and irreversibly attached to a surface. Since biofilms exhibit a high resistance against biocides, this project will develop a method to detect Staphylococcus aureus biofilms. In addition, several known and new biocides will be evaluated for their capacity to inhibit biofilm growth or to destroy existing biofilms.

Researcher(s)

Research team(s)

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.

Researcher(s)

Research team(s)

Investigation of antioxidant and antiviral natural products from medicinal plants for developing a complementary therapeutical strategy against HSV- and HIV-infections. 01/10/2002 - 30/09/2005

Abstract

In this research antiviral and antioxidant compounds will be isolated from medicinal plants in order to develop a complementary therapeutical strategy against HSV- and HIV-infections.

Researcher(s)

Research team(s)