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NAREB Report Summary

Project ID: 604237
Funded under: FP7-NMP
Country: France

Periodic Report Summary 2 - NAREB (Nanotherapeutics for antibiotic resistant emerging bacterial pathogens)

Project Context and Objectives:
Increase in antibiotic resistance is a global concern worldwide. The portfolio of available antibiotics for treating antibiotic resistant bacterial infections is very limited and comprises of molecules inducing severe side effects and/or difficult to administrate like aminoglycosides and vancomycin that require parenteral injection. New drugs or at least new formulations of known drugs that provide better efficacy are urgently needed for a faster, more efficient, and less impairing treatment.

In this context, the NAREB project aims to propose nanotechnology solutions to the problem of Multi-drug resistant (MDR) Mycobacterium tuberculosis (TB) as well as methicillin resistant Staphylococcus aureus (MRSA), two well-known drug resistant bacteria causing major public health problems in both developed and developing countries.

Several nanoformulations of current and novel antibacterial drugs (small molecules and biomacromolecules, such as glycopeptide-based molecules), and nucleic acid fragments delivery, intended to defeat resistance, were optimized to improve the therapy of MDR TB and MRSA infections in European patients. The nanocarriers and the drugs available from the NAREB consortium have already been separately tested for safety and toxicity. The combinations of drugs and nanocarriers will be tested in appropriate preclinical models, ending with a Clinical Development Plan for the preparatory work for the clinical trials of the developed products to be implemented after the end of the project.

To reach its objectives, the project NAREB brings together 16 partners (including 4 SMEs and 1 industry) from 8 EU Member and Associated States with outstanding complementary expertise, ranging from material engineering to molecular biology, pharmacology and medicine.
Over Period 2, the general objectives of NAREB were: 1. to investigate drugs selected during period 1, 2. to characterize their activity after formulation with nanocarriers, 3. to prepare batches of nanoparticles with their associated antimicrobial agents and reports of all physico-chemical and biological characterizations.
Project Results:
A number of antibacterial molecules among antibiotics used for the treatment of MDR TB or MRSA, new molecules showing anti-TB activity, drug candidates issued from high through put screening and transcription factor decoys (TFD) were chosen for encapsulation with nanoparticles, after a series of discussions between partners and medical microbiologists of the external advisory board.
Twelve leads issued from phenotypic screening of anti-tuberculosis drugs were analysed. Four of them were prioritized for encapsulation. Five other molecules have been identified as in vitro active leads in case of need. Drug targets and natural resistance mechanisms where successfully investigated for several of the new molecules tested.

Extensive efforts have been made to develop nanocarriers adapted to the loading antibacterial molecules. Four nanoparticle platforms have been considered based on lipid nanoparticles, on chitosan emulsions, on polyester copolymers particles and on polysaccharidic-base particles. The in vitro toxicity of the empty nanoparticles were evaluated to ensure their biocompatibility before use for drug delivery. Several cell lines were studied from specific (lung and epithelium) and unspecific target organs (blood cells and liver).

A large number of candidates (drug loaded nanoparticles) have been produced for M. tuberculosis and S. aureus, and they all have been tested for in vitro antimicrobial activity. A complete in vitro cytotoxicity profile was also generated for all candidates during the second period. Stability and interaction with cell lines has been characterised for most types of nanoparticles. Transcriptional response of human cells to treatment with nanoparticles has also been studied.

All these information have been decisive to select those progressing to in vivo assays. The work achieved so far allowed us to distinguish 3 nanotherapeutic candidates for MDR-TB and MRSA respectively, following a decision-tree based on the main criteria (loading properties, stability, activity and toxicity). Despite promising results obtained for the loading of TFD sequences, these TFD particles are on hold due to a lack of evidences about their efficacy.

In vivo experiments started as soon as the first nanotherapeutic candidates were available. These ongoing experiments include:
• Fluorescence optical imaging to evaluate in vivo biodistribution
• MS imaging in thin tissue cross-sections to study the biodistribution in the organs/tissues
• Pharmacokinetic of encapsulated and free drugs
• Efficacy of selected candidates
• Pre-clinical safety and immunocytoxicity of nanocarriers

New diagnostic tests based on qPCR and in CF-PCR-OC have been developed for M. tuberculosis and S. aureus. pPCRs is being used to evaluate the in vivo efficacy of nanotherapeutics in murine TB and MRSA models.

To select promising candidates for preclinical development, a landscape analysis questionnaire was develop to gather information related to the candidate, laboratory production process, evaluation in in vitro and in vivo studies, manufacturing considerations, etc. In addition, a product characterisation data sheet was also sent out. The information collected were analysed by the Product Development Team to advice on the selection of therapeutic candidates.
A Product Inventory System is a tool for portfolio management of product development, i.e. provide an ‘easy to review’ document to follow the progress of selected candidates. A template product inventory document was prepared and sent to partners with selected candidates for completion. This inventory document is a summary of information including target product profile, product characterization, quality & stability data, safety data, etc.

Regarding dissemination, the communication tools implemented in the first period of the project were updated, in particular the public website which was modified to include more information on the project. News related to the project or other events related to nanotherapeutics and infectious diseases are regularly published on the home page.
Since the beginning of the project, around 40 dissemination activities were conducted to present NAREB project and its results internationally to a wide range of public. Of particular importance is the dissemination workshop on “Novel Approaches to fight bacteria” co-organised with other projects funded by the European Commission.
The Business Committee met for the first time to identify the products/systems with good chances of exploitation.
Potential Impact:
NAREB project is expected to contribute to the development of new therapeutics which will be available to the European citizens. Confronted with the growing threat of MDR TB and MRSA infections, these new therapeutic approaches are expected to contribute to a cost effective control of TB and MRSA and reduce the financial burden of these infectious diseases to the health care systems.
We aim at designing at least one active formulation of an antimicrobial compound by using untargeted or targeted nanoparticles, the main criterion of success being an improvement of the MRSA or MDR-TB therapy in terms of efficacy and/or safety and lower toxicity (thanks to the concentration and targeted delivery of the active drugs). These improvements would increase the compliance of the patients, known to be key in the antibiotic resistance appearance.

Nanocarriers will contribute to a radical improvement of the therapy for bacterial infectious diseases by (i) targeting drugs to the infection site, thereby reducing total body dose and minimizing side-effects and by (ii) the option of simultaneously delivering multiple drugs, also combinations of antibiotics and nucleic acid therapeutics, targeting bacterial gene expression, thereby opening for highly innovative combination therapies. Work done has contributed to the characterisation of nanoparticles, by determining their antimicrobial properties and other basic biological features such as stability, etc. In addition to that, new diagnostic systems for quantifying the pathogens of interest, and for identifying genetic markers responsible for drug resistance are being fully developed.

If successful, the NAREB project will greatly contribute not only to better understand the interaction between pathogens and nanoparticles in a context of infection, but also to renew the interest of the applications of nanotherapeutics for fighting against infectious diseases, especially for overcoming the issues of resistance mechanisms to traditional antibiotics.

As a reminder, the World Health Organisation (WHO) has recognized antibiotic resistance as one of the three major threats to global health, and is predicting a forthcoming disaster due to the rapid, unchecked increase in antimicrobial resistance’ largely as a consequence of the paucity of new classes of antibacterials in development. Nanotherapeutics may considerably contribute to one of the major health related socio-economic and societal challenge, improving the patient’s quality of life and reducing the associated healthcare costs. Moreover, the applications of such nanoformulation of antimicrobial agents may also be extended to treat other infectious diseases.
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