Bioplastics are nowadays considered as a sustainable alternative to conventional polymers, especially for specific applications such as in agriculture which requires eco-friendly materials and, preferably, biodegradable polymers. EcoBioPlast will contribute to understand and to model the biotic and abiotic process of micro- and nano-bioplastics biodegradation and their impact on soil and aquatic ecosystems to conceive new efficient tools for integrated crop management, particularly for the development of more effective, stable, eco-friendly and with longer-acting plant protection products based on biocontrol agents. For this, EcoBioPlast will implement a multidisciplinary approach with the collaboration of two partners with expertise bio-based engineering polymers, plant biology, environmental microbiology and math expertises.

The IMOTEP (In silico MOdels of drug Transport to Enhance Personalized medicine) research project aims at building in silico molecular models of key pharmacological events of the patient response to multidrug treatments. A series of six human membrane transporters (solute carrier - SLC - and ATP-binding cassette - ABC transporters), namely OAT1/3, OATP1B1/1B3 and MRP2/4, will be constructed in silico by homology modeling techniques and molecular dynamics (MD) simulations to elucidate key structural features. Drug-transporter interactions will be studied by (static and dynamic) docking procedures, followed by MD simulations to explore the surrounding of the binding sites. The specificity (if any) of the substrate-transporter interaction will provide insights at the atomistic level, which will improve a knowledge which is currently highly fragmented. A series of prototypical substrate-drugs or drugs including those used in organ transplantation, as a representative clinical situation requiring multidrug treatments (e.g., cyclosporin, mycophenolic acid, nucleic acid-like antivirals, penicillin) will be docked in the six transporters. Special attention will be paid to drug-drug interactions (DDI) involving membrane transporters. Genetic variants will also be constructed to mimic frequent or rare single nucleotide polymorphisms (SNPs) or other mutations in the genes coding these membrane transporters and identified in patient samples stored in biological collections. The impact of point mutation on the protein structure will be predicted in silico and translated in terms of function of the drug transporter. The predictive capacity of the in silico models will be supported by in vitro experiments made on biomimetic models (mainly tethered lipid bilayer membranes - tBLMs), which will allow functional embedding of the different transporters and evaluation of drug transport. As a further step, the results observed in silico and in biomimetic models will be compared to in vitro experiments made with cell lines overexpressing the different transporters, namely HEK293T cells transitorily transfected with plasmids containing WT or variant (mutant obtained by site-directed mutagenesis) transporter genes. IMOTEP will be carried out by using a multidisciplinary expertise involving the young research host unit (INSERM U1248) but also biophysicists from Technology university of Compiègne partner (CNRS U7025) and theoretical chemists from Palacky University of Olomouc (RCPTM). The complementary expertise of the different partners will allow for a multiscale approach: from atoms to clinical situation. The linkages from atoms to patients (atom ? macromolecule ? cell ? organ ? patient) will be performed thanks to a dual approach. IMOTEP will be initiated by a top-down approach, in which well-defined clinical data about, e.g., DDIs and genetic variants will guide the creation of the in silico models. Once models are validated, they will be used in a bottom-up approach to enable simulating inter-individual variability of the pharmacological response as well as to understand and predict observed or suspected clinically relevant DDI mediated by membrane transporters. IMOTEP offers a unique opportunity to gather a consortium encompassing such a multiscale strategy dedicated to personalized medicine for organ transplant recipients. Organ transplantation is indeed a prototypical example for transporter-related DDI exploration, for which the young researcher’s unit has a long-lasting expertise in the related pharmacology, with an actual impact on clinical decisions. However, these models will be transferable to any pathology requiring multidrug treatments and/or in which similar membrane transporters are involved (e.g., chemotherapy, drug crossing the blood-brain barrier).

Heart failure is a major public health problem affecting 23 million people worldwide. Most of patients must be frequently monitored. Acute decompensated Heart Failure, defined as “gradual or rapid change in heart failure signs and symptoms resulting in a need for urgent therapy”, constitutes the main causes of rehospitalization in patients living with Heart Failure. The medical treatment are drugs, that requires approximately 4.5 months for patients’ conditions stabilization. The best of medical guidelines for the treatment of Heart Failure are however progressing quickly to enable them to be stabilized and kept in improving life conditions. However, it is tough to keep those patients at the best possible health levels as decompensations are often difficult to recover from and instabilities are creating many comorbidities and in pathology rapid health degradations. In order to cover this need, DYNABIO final target is a medical portable monitoring device able to ensure a continuous monitoring of the main HF biomarkers by using non-invasive biocompatible sensors. The device would allow the continuous monitoring of unstable patients without request to have frequent blood samples sent to analysis robots. It will combine the practical use of a telemedicine monitoring tool capable to copilot the patient health dynamically with the accurate measurement of main HF biomarkers from the sensors sampling in subcutaneous fluids or micro vascularized blood samples. The project will last 42 months with 3 axes of work, with the aim to provide all proof of feasibility required for the final target output of being able to create a large industrialization project from applied R&D, leveraging the project results: - Stream 1: Development to a sufficiently high TRL level (to create an industrialization plan) for the biocompatible molecularly imprinted materials targeted at the selected biomarker families; - Stream 2: Development to a sufficiently high TRL level (to create an industrialization plan) of a solution to integrate the material into a device using optical fibers for signal collection; - Stream 3: Validation and Industrialization Gate elements, with the aim to lift all the necessary elements of this feasibility study into an industrially applied project. The aim of this project is to develop the science-to-technology pre-requisites for a micro invasive device able to perform continuous monitoring. If this project is successful, the subsequent goal will be to raise the required resources (up to 20/30 M€) from private and collaborative R&D to finance industrialization. For that, the project is based on a largely used biomarker family and a sensor design with a strong IP creation potential. In fact, at the end of the project, BioSerenity, as the unique economic actor of the project, will have established a business case for the technological transfer of project innovations. In particular, public and private partners will have been identified for the industrialization of the product, as well as potential funders, in order to demonstrate its technical and economic viability, based on the exploitation of intellectual property resulting from the project. The DYNABIO project is supported by three organizations: - BioSerenity, a fast-growing innovative company which combines high tech engineering, medical development and big data analytics; - The Université de Technologie de Compiègne, a public research university located in Compiègne; - The Institut de Science des Matériaux de Mulhouse, a CNRS-University de Haute-Alsace mixed research unit located in Mulhouse. The total budget for the project is €1,135,644, with a requested funding of €575,598. The remaining part of the budget will be self-financed by BioSerenity.

The aim of MIPTIME is to detect and characterize binding events of single ‘antigen’ molecules to single nanoparticles of molecularly imprinted polymer (MIP)-based synthetic antibody mimics. While the properties of MIPs have been studied at the macroscopic level, the molecular proof through the characterization of single binding events is still missing. Within MIPTIME we will set a new experimental framework to study molecular interactions in MIPs and, more generally, in biomimetic nanomaterials. For this purpose, we will use fluorescently-labeled MIP nanoparticles (MIP-NPs) with oriented binding sites, synthesized using an innovative solid-phase synthesis approach, where antigen molecules are immobilized on a solid support in an orientated way. These specifically-developed MIP-NPs will enable us to answer fundamental questions regarding the number of binding sites in a MIP, their orientation homogeneity, the dynamics of single molecule binding events related to antigen size, and the functionality of bivalent and bi-specific MIPs. To this aim, we will use super-resolved fluorescence lifetime imaging microscopy at the single molecule level with ultimate spatial and temporal resolution thanks to an innovative method recently developed within the consortium. This will allow the guided evolution of nanometer-sized MIPs towards 'ideal' molecular biomimics.

NATURAL-ARSENAL (New Antibiotics Tackling mUlti-Resistance by acting on Alternative bacteriaL tARgets in Synergy with mEmbrane-disruptiNg AntimicrobiaL peptides) aims at characterizing the action of new classes of antibiotics from myxobacterial and actinobacterial strains in carpapenem-resistant Gram-negative bacteria, while potentiating their action by membrane-destabilizing antimicrobial peptides. Cystobactamids and Chelocardin derivatives are natural antibiotics that have escaped resistance-development over hundreds millions of years and which have been shown by one of us to be active against resistant clinical isolates, including P. aeruginosa and Klebsiella pneumoniae, commonly found in French and German Hospitals. Thereby, this project focuses on the development of new antibiotics inhibiting alternative bacterial targets and the understanding of their mechanism of action on a structural and biophysical level. In order to circumvent resistance development by mechanisms that imply reduced membrane permeability a combinatorial approach will be developed where antimicrobial peptides (AMPs) such as SAAP-148 or Frenatin 2.3S and Calethicidin-BF derived from frog skin assure the disruption of bacterial membranes with minimal effects on erythrocytes. The development of nanogels based on molecularly imprinted polymers (MIPs) opens the way to overcome the main limitations in the pharmacological use of antimicrobial peptides, while providing a mean to deliver them to the bacterial surface with the proposed antibiotics for a synergic action. As most natural antibacterial compounds, the Cystobactamids and Chelocardin derivatives act at multiple bacterial targets including the bacterial membrane, the ribosome, the DNA-gyrase and the efflux-pumps. NATURAL-ARSENAL involves top clinics and top structural biology laboratories in a common dialogue to elucidate the mechanism of action of promising new weapons against multi-resistant pathogens.