Sensiting Pseudomonas aeruginosa biofilms to antibiotic and reducing virulencce through novel target inhibition (SENBIOTAR)

The traditional approach to combating bacterial infections has been based on the use of antibiotics which kill bacteria or inhibit their growth. There has also been a strong emphasis on the identification of essential gene targets for drug intervention. A major problem with therapeutic approaches targeting viability is that they induce strong selective pressures resulting in the rapid emergence of antimicrobial resistance. An alternate approach is to inhibit virulence rather than bacterial viability and this will be explored in the SENBIOTAR project.

Completed project

In the opportunistic human pathogen Pseudomonas aeruginosa, virulence is co-ordinately controlled at the bacterial population level through quorum sensing (QS), a global cell-to-cell communication system employing diffusible signal molecules. P. aeruginosa strains with mutations in the Pseudomonas Quinolone Signal (PQS) QS pathway are avirulent in experimental animal infections. The partners of this consortium will exploit this information by optimising hit compounds and peptide nucleic acids (PNAs) they identified previously which target PQS biosynthesis and/or PQS signal transduction. These hits have been shown to not only render P. aeruginosa avirulent but also to sensitize biofilms to the action of antibiotics.

One of the limitations of using inhibitors of virulence is the fact that immunocompromised patients may not be able to clear the targeted pathogen efficiently. However, if the pathogen can, at the same time, be sensitised to antibiotics then there is great scope for dual therapy with PQS inhibitors and antibiotics. SENBIOTAR will bring together world experts in QS, medicinal chemistry, PNAs, drug delivery and preclinical studies to optimise the activity of the hit compounds and PNAs (hit-to-lead optimization) with the intention of identifying lead compounds which strongly inhibit QS, attenuate virulence and sensitise biofilms to conventional antibiotics at sub-micromolar concentrations. This will be achieved by improving (a) their physicochemical properties without the emergence of cytotoxicity, and (b) delivery to the site of infection. These studies will be performed using a combination of in vitro virulence and biofilm bioassays alongside experimental animal lung infection models. The lead compounds developed by SENBIOTAR will also have significant potential for the treatment of wound, bloodstream and medical-device associated infections caused by P. aeruginosa.

Project partners

  • Miguel Camara, University of Nottingham, United Kingdom (Coordinator)
  • Peter Nielsen, University of Copenhagen, Denmark
  • Roger Levesque, University of Laval, Canada
  • Christel Bergström, Uppsala University, Sweden

With the continuous raise of antibiotic resistance, it is becoming more difficult to treat some bacterial infections. SENBIOTAR has studied an alternative way to treat these infections and in particular those caused by the human pathogen Pseudomonas aeruginosa; one of the major pathogens worldwide. This organism possesses a language based on the use of chemical signals which controls the production of toxic products responsible for causing diseases and potentiates mechanisms conferring resistance to antibiotics. This chemical language is called ‘quorum sensing’.

In SENBIOTAR we have developed chemicals which do not kill this pathogen but interfere with this language, reducing the capacity of this organism to cause disease whilst making it more sensitive to antibiotics. New formulations have been developed for the delivery of these compounds to the site of infection using lab-based disease models and the results have been very promising. In addition, these compounds did not show any toxicity to human cells which means they have the potential to be developed into a novel treatments for human infections caused by P. aeruginosa.

Project resources

Coordinator Miguel Camara’s website



Investigating the mechanism of eradication of MDR bacteria by inorganic, organic, and protein-based nanoparticles (NPERDMDR)

The increase in nosocomial infections is adding a substantial burden to the medical system as they result in extended periods of hospitalization. This increase is strongly associated with the emergence of antimicrobial-resistant bacterial strains over the last two decades.The widespread use of antibiotics has resulted in the evolution and spread of these resistant genetic determinants: multidrug resistant (MDR) and extremely drug resistant (XDR) bacteria. There is an urgent need to develop novel antimicrobial agents to be able to kill antibiotic-resistant bacteria.

Completed project

Preliminary results show that inorganic mixed metal and that quorum sensing inhibiting enzyme (QSIE) NPs are effective in biofilm inhibition in pathogenic bacteria. We will investigate why these NPs are effective by studying clinical isolates of MDR bacteria in both planktonic and biofilm forms.

The proposed project brings together experts from Israel, Canada, and Spain. Gedanken will sonochemically synthesize and characterize MMO and ANB NPs. Tzanov will synthesize the QSIE NPs, study NP interactions with bacterial membrane models, and together with Banin will evaluate the efficacy of the of NPs against both planktonic and biofilm cultures. Bach will investigate the cytotoxicity and immunological response of the NPs in human cell lines and murine models infected with MDR bacteria, and develop a model of NP antibacterial mechanism using proteomics. Hafeli will perform pharmacokinetic analysis and NP distribution using bioimaging in murine models.

The significance of this project is to provide alternative antibacterial agents to tackle an emergent issue in our society.

Project partners

  • Aharon Gedanken, Bar-Ilan University, Israel (Coordinator)
  • Horacio Bach, University of British Columbia, Canada
  • Tzanko Tzanov, Universitat Politecnica de Catalunya, Spain
  • Ehud Barin, Bar-Ilan University, Israel
  • Urs Hafelli, University of British Columbia, Canada

Outbreaks of infectious diseases caused by pathogenic bacteria and the development of antibiotic resistance urges the development of new antimicrobial agents. Nanomaterials have emerged as novel antimicrobial agents because of their high surface area to volume ratio and the unique chemical and physical properties. It appears that their antimicrobial activity is exerted by a combination of different mechanisms, such as reacting with -SH protein groups, uncoupling respiratory electron transport, changing cell morphology, and causing cell membrane disruption and DNA damage .

There are four mechanisms by which bacteria exhibit resistance to antimicrobials: antibiotic inactivation/ modification, alteration of target site, alteration of metabolic pathway, and reduced drug accumulation. None of these mechanisms of resistance have been reported in nanoparticles (NPs) with antibacterial activity. It is thought that the acquisition of bacterial resistance to NPs will only occur if there were multiple protein mutations in a short period of time, which is highly unlikely. Moreover, studies have reported the antibacterial efficiency of NP against multidrug resistant (MDR) bacteria. Biofilm formation constitutes another mechanism that protects bacteria against antibiotics. This protective mode of growth occurs on either living tissues; including lungs, wounds and teeth, or non-living surfaces, such as medical implants and indwelling medical devices. Once formed, biofilms are difficult to remove as they are resistant to biocides and antibiotics when compared to planktonic bacteria. This is thought to be due to the physiological alteration of the bacteria upon attachments to the surface, as well as to cell specialization that may occur within biofilms.

Nevertheless, it is crucial to evaluate whether existing or newly developed nanoparticles (NPs) can inflict genetic changes within the bacteria that will ultimately result in resistance. Hence, one of our aims in the consortium was to develop assays that will allow determining the potential of bacteria to develop resistance to NPs developed and synthesized in the project.



New intervention strategy for tuberculosis: blocking multiple essential targets (noTBsec)

Mycobacterium tuberculosis is the causative agent of tuberculosis (TB), a disease responsible for almost 1.3 million deaths per year. In recent years, different classes of drug resistant M. tuberculosis strains have emerged, making the discovery of novel anti-TB drugs a major global priority. This awareness has resulted in several new initiatives to find new (classes of) antimicrobial compounds. One of these initiatives is NM4TB, a consortium containing two noTBsec members, which discovered the benzothiazinones as promising new antimycobacterial compounds. A major disadvantage of most existing and new TB compounds is that they target a single molecule, which significantly increases the chance that resistant strains will emerge.

Completed project

In this project, we will address this problem by identifying compounds that target multiple type VII secretion (T7S) systems. T7S systems are used by M. tuberculosis to secrete proteins across the cell envelope to the cell surface or into the host environment. Interestingly, this bacterium has several different T7S systems, three of which are essential for viability or virulence. We predict that, by blocking multiple T7S systems with a single compound, we will considerably reduce the development of drug resistance. To target T7S systems, we will use two complementary approaches to identify: (i) secretion blockers based on secretion activity assays and (ii) compounds designed to target specific T7S components.

As proof of principle, we have already successfully used the first approach to identify two different classes of compounds that block T7S systems. Importantly, one of these compounds significantly reduced mycobacterial growth in vivo. For the second approach we will exploit the detailed knowledge of T7S systems that has been recently generated within the consortium, including structures of several crucial druggable components. To increase the activities of our secretion-blocking compounds, we will also identify compounds that act synergistically with them from libraries of antibiotics and other FDA-approved drugs. Subsequently (combinations of) compounds will be tested in vivo in a high throughput animal model for activity, toxicity and resistance development. Together, these experiments will identify molecules inhibiting T7S secretion. These will be used to test the concept that by inactivating multiple essential targets, the emergence of drug resistance is reduced.

Project partners

  • Willbert Bitter, VU University Medical Center, Netherlands (Coordinator)
  • Roland Brosch, Pasteur Institute, France
  • Magnus Steigedal, Norwegian University of Science and Technology, Norway
  • Charles Thompson, University of British Columbia, Canada
  • Stewart Cole, Swiss Federal Institute of Technology Lausanne (EPFL), Switzerland



Repotentiating Beta Lactam antibiotics (REBEL)

The most common form of resistance to ß-lactam antibiotics is the expression of ß-lactamase enzymes. These bacterial enzymes are capable of inactivating ß-lactam drugs by hydrolyzing their ßlactam ring, rendering them ineffective. Co-administration of a ß-lactam antibiotic with a ßlactamase inhibitor is a recognized strategy to circumvent this type of bacterial resistance, yet the number of compounds that have actually made it to clinical application so far is extremely limited.

Completed project

The aim of this project is to discover and characterize new molecules of botanical origin that selectively inhibit ß-lactamases, yielding new lead compounds. Natural products from plants serve as rich resources for drug development, and the enormous structural diversity of plant derived compounds suggests that they may hold many more interesting pharmacological constituents. As a source of finding new ß-lactamase inhibitors however, they have remained largely unexplored. New ß-lactamase inhibitors will be obtained by systematically screening the PECKISH library (Plant Extract Collection in Kiel in Schleswig-Holstein). PECKISH is a standardized library containing more than 4600 unique aqueous, ethanolic and other extracts from > 860 different plant species (~190 different plant families) and 11 different plant tissues.

The screening strategy involves miniaturized agar-diffusion growth inhibition assays based on a range of modified E. coli bacteria expressing different (types of) ß-lactamases. Extracts showing ß-lactamase inhibitory activity will be profiled and a selection of the most promising extracts will be subjected to further isolation, identification and structural confirmation of the bioactive compound. After verification of the inhibitory capacity of the new compounds, design and synthesis of analogues will be initiated. Full characterization of the newly identified inhibitors and analogues using biochemical and crystallographic studies will be carried out.

Ultimately this project should yield the identification of new lead compounds for the development of clinical ß-lactamase inhibitors.

Project partners

  • Mariel Pikkemaat, RIKILT- Wageningen UR, Netherlands (Coordinator)
  • Natalie Strynadka, University of British Columbia, Canada
  • Fredrik Almqvist, Umeå University, Sweden

Resistance against β-lactam antibiotics is a serious health issue. Often it is caused by bacteria producing enzymes capable of inactivating these antibiotics, β-lactamases. This can be prevented by combining the antibiotic with a compound able to inhibit the bacterial enzyme.

The aim of this project was to find new β-lactamase inhibitors. To achieve this a large botanical extract was screened for β-lactamase inhibitory activity, and several compounds were isolated and identified. Further research on these compounds is needed to determine their suitability for medicinal application, and ultimately to effectively fight β-lactam resistant bacteria.


Structure-guided design of pan inhibitors of metallo-p-lactamases (DesInMBL)

The fight against infectious diseases is one of the greatest public health challenges, especially with the emergence of pan-drug resistant carbapenemase-producing Gram-negative bacteria. In particular, the pandemic NDM-1 and other plasmid-borne metallo-ß-lactamases (MBLs) disseminating worldwide in Gram-negative organisms threaten to take medicine back to the pre-antibiotic era as the treatment options remaining for infections caused by these “superbugs” are very limited.

Completed project

The aim of the present proposal is to combine complementary approaches (microbiology, biochemistry, structural biology, molecular modelling and chemical synthesis) to gain vital insights into structure-function relationship of MBLs, in order to better understand substrate specificities, to determine key residues involved in carbapenem recognition and hydrolysis, to foresee the impact of mutations on the hydrolysis profile, and finally to develop an efficient MBL pan inhibitor.

In-depth biochemical characterization of broad-profile MBLs and co-crystallization of these enzymes with various ligands will provide crucial information for the development of efficient inhibitors that could serve as leads in drug discovery. Site directed mutagenesis will be used to confirm the role of key amino-acid residues in the active sites of the enzymes. With the increasing prevalence of MBLs, new variants will be described, with likely modified hydrolysis properties, which will provide further information on the role of different active site residues. Recently, a novel MBL inhibitor capable of efficiently inhibiting NDM-1 (sub-micromolar IC50) was identified by Partners 1 and 3, using a combined approach of docking and pharmacophore-based virtual screening of focused ligand libraries.

We will take advantage of this discovery and use two strategies to obtain an MBL pan inhibitor: i) structure- and function-guided optimization of the previously identified inhibitor in order to ensure efficient inhibition of most or all MBLs, using the data gathered during this project; ii) identification of new pan inhibitors of MBLs using a consensus pharmacophore common to all clinically-relevant MBLs. Our results will advance the development of pan inhibitors of MBLs that, used in combination with ß-lactams, will protect the ß-lactam antibiotics from degradation by these MBLs.

Project partners

  • Thierry Naas, University Paris Sud, France (Coordinator)
  • Youri Glupczynski, CHU Dinant Godinne UCL, Belgium
  • Bogdan Iorga, CNRS, Institut de Chimie des Substances Naturelles, France
  • Mariusz Jaskolski, Institute of Bioorganic Chemistry, Polish Academy of Sciences (IBCH PAS), Poland

The fight against infectious diseases is probably one of the greatest public health challenges faced by our society. The pandemic NDM-1 and other plasmid-borne metallo-ß-lactamases (MBLs) disseminating worldwide in Gram-negative organisms threatens to take medicine back into the pre-antibiotic era since the mortality associated with infections caused by these “superbugs” is very high and the choices of treatment are very limited.

The aim of the present proposal is to combine complementary approaches (microbiology, biochemistry, structural biology, molecular modelling and chemical synthesis) to gain vital insights into structure-function relationship of MBLs, in order to better understand substrate specificities, to determine key residues involved in carbapenem recognition and hydrolysis, to foresee the impact of mutations on the hydrolysis profile, and to develop an MBL pan inhibitor. In-depth biochemical characterization of broad and narrow-spectrum MBLs and their mutants have provided crucial information on the key residues in involved in ß-lactam hydrolysis, and for the development of efficient inhibitors that could serve as leads in drug discovery. Along with the increasing prevalence of MBLs, new variants have been described, with modified hydrolysis properties, which provides further information on the role of different active site residues.

Finally, we have developed a novel MBL inhibitor capable of efficiently inhibiting NDM-1 (100nM IC50) but also VIM and IMP. Two strategies were used to obtain this MBL pan inhibitor: i) structure- and function-guided optimization of a previously identified inhibitor, using the data gathered during this project; ii) identification of new pan inhibitors of MBLs using a consensus pharmacophore common to all clinically-relevant MBLs. Our results have advanced the development of pan inhibitors of MBLs that, used in combination with β-lactams, will protect the β-lactam antibiotics from degradation by these MBLs. Finally, we have developed a unique database on ß-lactamases.

Project resources



Non-conventional approaches for peptidoglycan cross-linking inhibition (NAPCLI)

Peptidoglycan (PG) is an attractive and validated target for antibacterial drug development for two main reasons. First, it is an essential and unique bacterial cell wall polymer with no counterpart in human cells, minimizing the risk of drug toxicity. Second, the essential PG synthases are exposed at the outer surface of the cytoplasmic membrane, making them highly accessible for antibiotic inhibition.

Completed project

Formation of the PG network requires glycosyltransferases for glycan chain elongation and transpeptidases for peptide cross-linking. Transpeptidation involves two stem peptides that act as acyl donor and acceptor substrates, respectively. The acyl donor site is targeted by the ß-lactams, which form covalent adducts, and this interaction is well characterized. In contrast, nothing is known on the interaction of the transpeptidases with the acceptor substrate. To combat the erosion of the activity of ß-lactams, we propose to identify additional drugable sites in the transpeptidases, including the acceptor binding site, and develop lead antibacterial agents acting on these sites.

Our first objective is to characterize the mode of recognition of the acyl acceptor by transpeptidases and identify compounds blocking the binding of this substrate. We will use NMR spectroscopy to map the acceptor site and develop specific inhibitors based on modeling and virtual screening. Our second objective is to identify the partners of transpeptidases that regulate the coordinated elongation of glycan chains and cross-linking of stem peptides. This will allow us to select additional drugable sites in transpeptidases and associated proteins within the PG polymerization complexes.

We will map key interactions by FRET analyses in live bacteria producing fluorescent proteins and by in vitro transpeptidase/glycosyltransferase assays in complexes obtained by tandem-affinity purification. Microfluidic cultures and time-lapse microscopy will assess the impact of inhibitors on cell division and viability. The interaction of lead compounds with their targets will be characterized by X-ray crystallography. These complementary approaches will enable the consortium to develop novel strategies for transpeptidase inhibition and obtain leads active against ß-lactam-resistant bacteria.

Project partners

  • Michel Arthur, INSERM, France (Coordinator)
  • Waldemar Vollmer, Newcastle University, UK
  • Tanneke den Blaauwen, University of Amsterdam, The Netherlands
  • Jean-Pierre Simorre, CNRS, France
  • John Mc Kinney, Swiss Federal Institute of Technology Lausanne (EPFL), Switzerland
  • Natalie Strynadka, University of British Columbia, Canada

Antibiotics gradually lose their efficacy due to the emergence and dissemination of resistance in all bacterial pathogens. At the same time, most pharmaceutical companies have disengaged from the development of new drugs since it is not profit-making. In this context, efforts for early steps of drug discovery have partly moved from industry to academic laboratories.

Bacterial resistance to antibiotics is by no means a new issue. It has been mainly fought by modifications of molecules discovered more than 50 years ago. Consequently, antibiotics available in the clinics belong to a very limited number of chemical classes. It is arguable that modification of these drugs to escape resistance has reached, or will soon reach, an unbreakable limit since resistance mechanisms are able to promptly evolve to be effective on drugs with similar structures and the same mode of action.

The JPIAMR-funded project has evaluated new ways to inhibit “old” drug targets. We focused on the targets of penicillin, which have been validated by a long history of successful antibiotherapy. Our consortium brought together research teams with complementary expertise in structural biology to identify new drug binding sites, in chemistry to synthesize molecules specific of these binding sites, and in biochemistry to evaluate target inhibition. By this approach, we have identified new binding sites that are distinct from that of penicillin and are essential for the activity of the targets.

Project resources

Research spotlight: One-pager on NACPLI (pdf 0,2 MB)



Capturing the natural antibiotic’ome: Developing Nature’s EVOIved AntiBIOTIC Collective (EVOBIOTIC)

Naturally evolved antibiotics are our primary mode of treating drug-resistant pathogens. Although individual antibiotics do succumb to resistance via pressures they place on organisms, the producers of these agents innovate through modular antibiotic drug (bio)synthesis programs to naturally thwart drug resistance mechanisms.

Completed project

Moreover these same antibiotic drug biosynthesis programs, are now revealed to construct other agents that perturb microbial physiology apart from killing (i.e. blocking resistance). The evolutionary constraints that have produced these evolved genetically encoded natural drugs are difficult to envision but their specificities, dynamic actions, multi-pronged functions have clearly rendered them as privileged molecules.

Much research has defined the codes embedded within these natural small molecule biosynthesis programs and surprisingly these codes and rules are largely followed across all known organisms that generate polyketide and nonribosomal peptide molecules. In addition to the cracking of the nonribosomal and polyketide codes, further facilitating their genomic-based identification is the clustering of genes associated with the synthesis of a particular molecule-type (natural product/antibiotic) and a collinear pattern used in their synthesis. Collectively, these natural principles and rules have now created an exceptional opportunity to drive the detection and discovery of these molecules using a genomic start point.

New transformative approaches to antibiotic discovery are needed, and the research in this proposal will lead to disruptive innovation, and a major departure in how historically antibiotics have been found and investigated. With our unique approaches we will enrich in agents with new modes of action, and those with a high likelihood of synergizing with clinically used antibacterials.

The following aims are designed to provide this forward-looking view of how to treat antibiotic resistant bacteria:

  1. Uncover the secondary metabolomes of antibiotic producers and define antibiotic chemical-chemical interactions and synergy.
  2. Interrogate the bioproduction of antibiotics from genomically identified unexplored microbes using metabolomics.
  3. Test naturally evolved drugs against secretion systems and serum resistance systems of gram negative/drug-resistant organisms.

Project partners

  • Nathan Magarvey, McMaster University, Canada (Coordinator)
  • Julian Davies, University of British Columbia, Canada
  • Eliora Ron, Tel Aviv University, Israel
  • Raymond Andersen, University of British Columbia, Canada
  • Jean-Luc Pernodet, Paris-Sud Université, France
  • Gregory Challis, University of Warwick, UK

How much does antimicrobial resistance cost? The overall worldwide cost attributable to it is certainly high, but remains largely unknown. The economic studies performed so far only consider direct costs associated with human infection from a hospital perspective, primarily from high-income countries. But antimicrobial resistance is a One Health issue: it applies to human, animal, and environmental health.

We have developed a framework, called The Global Antimicrobial Resistance Platform for ONE-Burden Estimates (GAP-ON€), that shows the immense number of often hidden, human, animal and environmental costs across the many individual and societal dimensions, inextricably linked together in a One Health picture. There are many bacteria (but other germs as well) that can colonize or even cause disease in human beings and animals, in a common environment. These cause direct health costs (costs of medicines, hospital stay, diagnostic tests, etc) and also indirect costs (loss of working days, loss of farm animals in the food chain, insurance costs etc). Building on this framework, future studies will be able to assess more precisely what the costs of antimicrobial resistance are, and will hopefully increase global public awareness of the real burden of AMR in all areas of life, across the world.



InnovaResistance: Innovative approaches to address antibacterial resistance

The dearth of new bactericidal or bacteriostatic drugs entering the clinic and the emergence of infections due to multi-antibiotic resistant bacteria requires international collaboration supported by substantial financial investment. New drugs and/or therapeutic approaches are urgently needed to control bacterial infections and safeguard the health of populations.

The primary aim of this first joint call of JPIAMR is to combine the resources, infrastructures, and research strengths of multiple countries in order to overcome antibiotic resistance. The goal is to foster multinational translational research collaborations that can accomplish more than individual countries working independently, leading to improved control of bacterial infections.

It is expected that through international collaborations that combine complementary and synergistic research strengths, this JPIAMR call will facilitate the generation and application of new approaches to overcome antibiotic resistance.

Call Topics

The call will cover research addressing the following topics:

  • Re-evaluation of existing anti-microbial compounds either alone or in combination with other drugs, immune-modulators or anti-bacterial approaches.
  • Identification of new bacterial targets and/or therapeutic compounds in combination with point-of-care
    companion diagnostics where relevant.
  • Discovery and implementation of novel therapies to overcome known antimicrobial resistance mechanisms
    and restore susceptibility to conventional antibiotics. Examples might include studies on novel enzyme or efflux pump inhibitors, as well as studies aimed at understanding and overcoming the mechanisms controlling the generation of resistance.
  • Strategies for optimization of drug use, dosage and delivery of new drugs or drug combinations.
  • Strategies to inhibit or reduce the acquisition of resistance such as single molecular agents effective against multiple targets as well as therapeutics that enhance immune pathogen elimination, disrupt colonization, biofilm development, and virulence.

Following sub-topics are not in the purpose of the call:

  • Assessing the role of commensal flora in homeostasis and microbe’s pathogenicity, and elucidating how
    commensal organisms or probiotics can be used to prevent or treat infections.
  • Investigating the initial steps of the infection process.
  • Late stage clinical trials (Phase II and further).

Information & application

This call is closed.

Research spotlights from this call:


The Research Foundation – Flanders (FWO)
Fund for Scientific Research (FNRS)

Canadian Institute of Health Research (CIHR)

The Danish Council for Strategic Research

French National Research Agency (ANR)

Chief Scientist Office, Ministry of Health

The Netherlands
The Netherlands Organisation for Health Research and Development (ZonMw)

The Research Council of Norway (RCN)

National Science Centre

Instituto de Salud Carlos III

Swedish Research Council (SRC)

The Scientific and Technological Research Council of Turkey (TÜBITAK)

United Kingdom
Medical Research Council (MRC)

Supported projects

Seven projects were awarded funding within the JPIAMR first joint transnational call: “InnovaResistance: Innovative approaches to address antibacterial resistance”. Click on the project titles in the list below to learn more about each project.