One of the most challenging problems related to implanted medical devices is the high prevalence of microbial infections. Previous studies showed that implant-related infections are often caused by biofilm forming microbes. In contrast to infections caused by free-floating microbes, biofilms generally increase the tolerance to antimicrobials and increase the risk for antimicrobial resistance development.
The TRA-COAT project aims to address the incidence of implant infections by developing a novel, resistance-proof antimicrobial coating with innovative functionalities, including antibiofilm activity and triggered on-demand release of classic antimicrobials. The focus will be on orthopaedic trauma implants and vascular grafts, but can later be extended to other implants.
The coating will combine a covalently bonded biofilm inhibitor and a reversibly bonded classic antimicrobial. The action of the inhibitor will reduce the slimy matrix production during biofilm formation which will allow the immune system to better remove the microorganisms. If biofilm should still remain, growth of the bacteria on the surface will locally trigger release of the antimicrobial, killing the pathogens.
The coating is designed to be resistance-proof. Indeed, the biofilm inhibitors are intrinsically robust to resistance and will enhance the effectivity of the classic antimicrobial. The local and time-restricted release of the antimicrobial will reduce the risk of resistance development and benefit the patient.
- Hans Steenackers, Katholieke Universiteit Leuven, Belgium (Coordinator)
- Stephan Zeiter, AO research institute, Switzerland
- Annette Moter, Charité – Universitaetsmedizin Berlin, Germany
Bacterial infections caused by carbapenemase-producing Enterobacterales are a major health problem. One of the few treatment options is the new antibiotic ceftazidime/avibactam. However, relapse of infection may occur with associated resistance development.
Use of continuous infusion and combination therapies, in particular the addition of an old antibiotic, fosfomycin, to ceftazidime/avibactam, seem to be associated with improved outcomes. Indeed, in laboratory models, adding fosfomycin can lead to synergistic bacterial killing and less development of resistance to ceftazidime/avibactam. Yet, the dosing rationale is unclear; currently, massive doses of up to 24 g of fosfomycin are used, frequently leading to sodium overload.
The aim of the present project is to define and implement a rational dosing regimen for the combination of ceftazidime or ceftazidime-avibactam with fosfomycin against Enterobacterales. We will use state-of-the-art preclinical pharmacokinetic/pharmacodynamic (PK/PD) models (hollow-fiber, humanized-PK mouse model) with patient-derived bacterial isolates and PK to define optimised dosing regimens. Using whole genome sequencing/artificial intelligence, we will define the link between genetics and phenotypic bacterial susceptibility as well as synergistic effects, which could be developed into a rapid test to quickly identify patients who will benefit most from optimised combination therapy. Lastly, we will implement the optimised, pharmacometrics-guided dosing approach in a proof-of-concept controlled trial.
- Sandrine Marchand, Inserm U1070, France (Coordinator)
- Sebastian WICHA, University of Hamburg, Germany
- Jacob Moran-Gilad, Ben Gurion University of the Negev, Israel
- Angela Huttner, University of Geneva / Geneva University Hospitals, Switzerland
- Fernando Docobo-Perez, University of Sevilla / Hospital Virgen Macarena, Spain
- Maddalena Giannella, IRCCS Azienda Ospedaliero/University Alma Mater Studiorum of Bologna, Italy
Staphylococcus aureus is a common commensal bacterium with reservoirs in healthy individuals. However, infections due to S. aureus are notoriously difficult to treat in health-compromised individuals, especially if bacteria are antibiotic-resistant, and/or if antibiotics fail to reach the infected area.
Much current research aims at finding new antibiotics, repurposing old drugs, and developing combination therapies. However, drugs that work in the lab may not work in real infection situations, and efforts need to address drug functionality in the host, and its access to infected areas.
The current project combines these two objectives. It relies first on the development of a bi-therapy approach in which one antibiotic reaches its target and lowers virulence factor production, and another reinforces killing of the weakened bacteria. The most potent pre-selected bi-therapy couples will be enveloped in nanoliposomes, which are potent carriers already proven effective in various clinical treatments, including vaccines (like Covid), and for antibiotic delivery. Efficacy testing of bi-therapy, freely administered or encapsulated inside nanoliposome carriers, will be done in chronic and fulminant infection conditions. This study is unique in that it provides unique bi-therapy couples and confronts the difficulties of antibiotic access in both types of potential S. aureus infections. The use of known drugs will accelerate applications of our findings.
- Alexandra Gruss, Micalis Institute University Paris-Saclay, National Research Institute for Agriculture, Food & Environment, France (Coordinator)
- Patrick Trieu-Cuot, Institut Pasteur, France
- Lorena Tuchscherr, Jena University Hospital, Germany
- Asmaa Tazi, Institut Cochin, France
- Pablo Taboada, University of Santiago de Compostela, Spain
This project presents an innovative chemical tool to be applied to known cyclic peptide antibiotics.
The rationale of the design consists of maintaining the overall structure of the antibiotic to preserve the antibacterial activity while the presence of the chemical tool within the peptide backbone would facilitate the initial metabolization and detoxification by oxidorreductases upon eventual accumulation of the antibiotic in the kidney. The project follows a proof-of-concept scheme involving the necessary chemistry to prepare the model compounds, the in vitro and in vivo assays to assess activity and low toxicity, and estimate a therapeutic window. Finallly, tests to prove the design hypothesis and the mechanism of action at the membrane level are also proposed.
- Francesc Rabanal, Universitat de Barcelona, Spain (Coordinator)
- Matilda Bäckberg, RISE Research Institutes of Sweden, Sweden
- Pawel Baranczewski, Uppsala University, Sweden
- Edgars Liepinsh, Latvian Institute of Organic Synthesis, Latvia
- Timothy R Walsh, University of Oxford, United Kingdom
- Carina Vingsbo-Lundberg, Statens Serum Institut, Denmark
- Klaus Skovbo Jensen, CANDOR Simulation, Denmark
The massive scope of antimicrobial resistance (AMR) has prompted scientists to investigate alternatives to antibiotics for the treatment of patients afflicted by multidrug-resistant (MDR) bacteria. We have designed a unique inhibitor of the copper P-type ATPase, 3A11, and developed it to its preclinical phase.
We have shown it to be effective against several major Gram-positive pathogens, including MDR bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE). This is of great importance, due to the current lack of treatment options for VRE infections. To test the efficacy of our inhibitor, 3A11, against a plethora of strains, a vast panel of clinical isolates from the repositories of the project partners will be studied. The antimicrobial effects of 3A11 against this panel will be assessed and investigated in vitro to better understand the underlying molecular mechanisms of action. Additionally, to have a better model of the interactions between 3A11 and host cells, the bactericidal effects of this inhibitor will be analysed both in human cells and in mice.
A better understanding of the effects of 3A11 on bacterial cells and its molecular mechanisms of resistance will assess the suitability of this inhibitor as a non-antibiotic agent in the fight against AMR.
- Shilpa Ray, Karolinska Institutet, Sweden (Coordinator)
- Gerard Lina, Centre International de Recherche en Infectiologie, France
- Vincent Cattoir, University of Rennes 1, France
- Anne Santerre Henriksen, Maxel Consulting ApS, Denmark
- Anders Rhod Larsen, Statens Serum Institut, Denmark
Bacteria and other disease-causing organisms that can no longer be controlled or killed with medicines are called multidrug-resistant organisms (MDROs). MDROs pose a major problem to the healthcare system as they can cause severe infections and affect the weakest, in particular young children, the elderly or people with health conditions such as chronic lung, heart, and kidney disease.
In Europe, MDROs cause approximately 670,000 infections per year. 33,000 patients do not survive the infection due to the lack of treatment options.
Our aim is to develop a much-needed new strategy for the treatment of MDROs. To this end, we have designed a ‘nitroxoline shuttle’. Nitroxoline is an antibiotic drug that effectively kills a broad variety of bacteria; however, its use is limited to bladder infections due to its inability of reaching other parts of the human body. The ‘shuttle’ is a chemical substance that, when linked to nitroxoline, will allow to safely transport this powerful antibiotic to bacteria in various parts of the human body. In the project, we will manufacture the ‘nitroxoline shuttle’ and carry out tests to characterise its ability to kill bacteria in a targeted manner.
- Thomas Wichelhaus, Goethe-University, Germany (Coordinator)
- Kerstin Sander, University College London, United Kingdom
- Heiko Herwald, Lund University, Sweden
- Eugen Proschak, Goethe University, Germany
Multidrug resistance is a major problem in Candida auris, the first pathogenic fungus officially considered an urgent antimicrobial resistance threat by the CDC, and in Candida glabrata, which accounts for 20-40% of all systemic Candida infections. Antifungal resistance often leads to treatment failure, which significantly reduces survival rates of lethal candidiasis. Meanwhile, the antifungal drug market comprises only four classes.
By evolving C. auris and C. glabrata in different drugs and mapping their responses to other drugs, we have discovered collateral sensitivity (CS) and cross resistance (XR). CS is the process in which the acquisition of drug resistance towards one drug, confers an increased sensitivity towards another drug. Conversely, XR confers reduced susceptibility to more than one drug upon exposure to one drug. Information regarding the evolutionary tendencies of pathogenic fungi can be leveraged to improve therapeutic approaches for treating fungal infections. Both CS and XR have been studied extensively in tumors and in bacteria but remain unexplored in fungi. In this study, we will explore novel treatment schemes that have the potential to prevent the development of antifungal drug resistance in MDR species of most concern: C. auris and C. glabrata.
- Patrick Van Dijck, Katholieke Universiteit Leuven, Belgium (Coordinator)
- Katrien Lagrou, University Hospitals Leuven, Belgium
- Johan Maertens, University Hospitals Leuven, Belgium
- Micha Fridman, Tel Aviv University, Israel
- Juan Antonio Gabaldon Estevan, Institute for Research in Biomedicine, Spain
- Berman Judith, Tel Aviv University, Israel
Rapid increase of resistant bacterial infections is a major public health threat. Hence exploration of alternative treatment procedures including development of nanomaterial based therapeutic strategies is receiving much attention. Multi-resistant bacterial strains and biofilm formation are major causes of healthcare associated infections including complicated surgical site infections, infections of skin and soft tissue. Purulent wounds are associated with microbial persistence that alters healing and can lead to septic complications.
VARIANT aims to utilize three types of silver-based nanocomposites, Ag/CaO, Ag/ZnO, chlorhexidine + Ag nanoparticles (NPs), which have previously demonstrated antibacterial effect in vitro and in vivo. By combination and integration of these nanomaterials into the novel nanofibrous wound healing patches the project aims to improve the application, efficacy and delivery of antimicrobials lowering the tendency of antimicrobial resistant bacteria to form biofilms and minimizing the risks of blood stream infections. The new patches are expected to lack toxic impact and have advanced biocompatibility and controlled degradation time. They will be based on poly(lactic-co-glycolic acid) (PLGA)-chitosan electrospun scaffolds and compared with the existing commercially available bandages, patches and antibiotics to estimate their antibacterial efficacy against MRSA in a mouse model. Unlike the conventional antibiotics, Ag NPs based therapeutic agents are expected to overcome the formation of biofilms and mechanisms of bacterial resistance.
- Joerg Opitz, Fraunhofer Institute for Ceramic Technologies and Systems IKTS, Germany (Coordinator)
- Maksym Pogorielov, University of Latvia, Latvia
- Rafal Banasiuk, NanoWave, Poland
- Cecilia Stålsby Lundborg, Karolinska Institutet, Sweden
Mycobacterium abscessus (Mabs) is an emerging opportunistic pathogen responsible for lung infections particularly in cystic fibrosis patients. These infections are challenging worldwide due to their increasing incidence, their extreme resistance to available antimicrobial agents.
The lack of new efficient antibiotics forces researchers and clinicians to optimize treatments with existing antibiotics, generally by combining several molecules together. In order to do so, using innovative approaches like organoids to study antibiotic efficacy are needed. Human lung organoid is a 3D cell clusters organized into organ-like constituting unprecedented innovative tools to evaluate antibiotic efficacy against Mabs by taking into account the CF lung environment allowing study and then limiting the use of animals. This approach coupled to mathematical simulations to optimize the concentration of antibiotic to use and to the understanding of Mabs resistance development during treatment will also bring new information to know whether to associate the different antibiotics together.
The objective of the ACOMa project is to improve the treatment of patient by optimizing antibiotic combinations by implementing innovative approaches coupling the use of lung organoid with semi-mechanistic PK/PD models.
- Julien Buyck, INSERM U1070 “Pharmacology of Antimicrobial Agents and antibioResistance”, France (Coordinator)
- Peter Sander, Universität Zürich, Switzerland
- Céline Cougoule, Institute of Pharmacology and Structural Biology, France
- Nicola Ivan Lore, Ospedale San Raffaele, Italy
- Lucas Boeck, Basel university, Switzerland
Our body’s branching airway system that delivers oxygen deep into our lungs presents an effective barrier to protect our lungs from contaminants in the air, such as dust, pollen, and pollutants, but also bacteria and viruses.
The same barrier that protects us from inhaling unwanted matter also presents a considerable hurdle in using the human airways as an effective route of drug delivery. A variety of respiratory diseases benefit from inhaling a drug to route its active ingredient directly to its desired location in the human lung, rather than taking a detour through the stomach or blood circulation. Respiratory infections by bacteria, also known as bacterial pneumonia, can turn into life-threating conditions that could more easily be cured with powerful antibiotic inhalations. A complicating factor in the development of inhaled antibiotics is the fact that large amounts of antibiotics need to be applied, of which only a fraction end up at the actual site of infection.
Attempts to improve existing inhalation technologies have seen some progress in recent years. The APRINHA project aims to leverage on some of these achievements to study and compare a variety of novel formulation technologies using the new antibiotic apramycin as a promising case study. Apramycin is expected to be perfectly suited for such studies because it belongs to a drug class that has already been shown to be suited for inhalation. The project aims to develop an antibiotic inhalation with high penetration, deposition, retention, and efficacy of drug, so as to more effectively cure pneumonia patients.
- Sven Hobbie, University of Zurich, Switzerland (Coordinator)
- Dorothee Winterberg, Fraunhofer Institute for Toxicology and Experimental Medicine, Germany
- Iraida Loinaz, CIDETEC, Spain
- Frédéric Tewes, INSERM U1070, France
- Edgars Liepins, Latvian Institute of Organic Synthesis, Latvia
- Anna Fureby, RISE Reaserch Institute of Sweden AB, Sweden
- Per Gerde, Inhalation Sciences Sweden AB, Sweden