AMIS - Antimicrobials by immune stimulation

EC contribution: : € 2.100.000
Duration: : 36 months
Starting date: : 01/01/2005
Funding scheme: : Specific Targeted Research Project
Keywords: : immunology, infections, novel antimicrobial approach, immune stimulation, fusion compounds
Contract/Grant agreement number: : LSHM-CT-2004-512093
Project web-site: : -

Background:

AMIS aims to use the strength of our own innate immune system to design antimicrobial drugs for future generations. Antimicrobial proteins in our immune system are often combined with inflammatory signals in one single molecule. AMIS will take that same approach and reshuffle different parts of different molecules to make novel effector molecules that still have these combined functions but are optimally adapted for therapeutic intervention. Within our innate immune system many molecules have been identified over the last years that are involved in direct or indirect clearance of bacteria. The consortium will select the most promising and innovative compounds with this dual mode of action and:

Design proteins with anti-microbial activity in combination with an inflammatory trigger, targeting extra cellular bacteria;
Design proteins with inflammatory priming capacity (without extra anti-microbial activity); targeting intracellular bacteria;
Discover new modulators to dampen inflammation.

Problem:

The tremendous success with which antibiotics have been used to combat infectious diseases is under serious threat from the increasing development of antimicrobial resistance. Without new treatment approaches to address antimicrobial resistance, this threat will continue to rise. To fight infectious diseases effectively in the future we have to broaden the approaches in therapeutic intervention. There are three ways along which the therapeutic intervention of infectious diseases can be broadened. The first is to design drugs that have a smaller chance for resistance-development (to target evolutionary conserved structures is one key element here). The second is to design drugs that are as different in mechanism of action as we can envision. The third is to combine drugs. AMIS (Antimicrobials by Immune Stimulation) combines these three strategies in a highly innovative approach.

Aim:

Activators, receptors, effectors and inhibitors are an integral part of the complex mechanism of interaction in the innate immune system, combining cellular stimulation and anti-microbial action. These interaction mechanisms form the core focus of the research project envisaged by the consortium. The underlying theory is that the multitude of triggers needed to get a full-blown immune response is an intrinsic prerequisite to keep the process localized. That is why we will aim at subtle immunostimulation or priming, which will, in bacterial infections, be accompanied by an extra trigger, locally provided by the bacterial products at the site of infection. In its pursuit of a novel approach to address antimicrobial resistance, the consortium has formulated three main research objectives.

Expected and obtained results:

Make an array of fusion proteins that combine strong antimicrobial with inflammatory signals so that these two actions work in concert. By combining the best that we can find in our innate immune system we can tune the new molecules to perform better in certain specific infections than Nature has provided so far. Furthermore we aim to learn from our innate immune system how to effectively recognize and kill a bacterium for millions of years without developing major resistance.

Potential applications:

The collaborative research in AMIS will lead to proof-of-principle for a novel treatment approach to address antimicrobial resistance by combining the innate immuno-stimulation with the antimicrobial capacity of naturally occurring substances of the human innate immune system. Parts of that system have been proposed and tried before with antimicrobial peptides from insects and other species and activation of the immune system by bacterial compound [Toll Like Receptor (TLR) ligands or small molecules that affect the signalling pathway of TLRs] as examples. However toxicity in the first example and over-activation of the immune system combined with redundancy in the second example are inherent drawbacks in these alternative approaches.

Coordinator:

Dr Jos van Strijp
University Medical Centre Utrecht
Eijkman Winkler Institute
Heidelberglaan 100
3584 CX Utrecht, Netherlands
Tel. +31 302506528
Fax +31 302541770
E-mail: j.vanstrijp@azu.nl

European Commission