From the "arsenal" of natural antibiotics evolutionarily optimized during hundreds of millions of years, the group of Rolf Müller at Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) have selected cystobactamids and chelocardins produced by myxobacterial and actinobacteria (chelocardin derivatives) tageting bacterial membrane, ribosome, and gyrase. By switching on and off bacterial genes different variants of antibiotics can be produced to overcome resistance.

In order to reach intracellular targets antibiotics must be able to penetrate the bacterial membrane. Antimicrobial peptides (AMPs) are additional weapon of the natural "arsenal" able to dissolve or pierce bacterial membranes. SAAP-148 and Cathelicidin-BF from frog skin were selected for their low hemolytic properties. The group of Burkhard Bechinger at the University for Strasbourg has made important contributions to the understanding of their mechanism of action by solid-state NMR. The group of Nicola D'Amelio at University Picardie Jules Verne (UPJV) has created the ADAPTABLE web-served gathering more than 40000 AMP sequences. An alternative way of synthesizing AMPs by phage display will be tested by the group of Berangère Avalle at UTC of Compiegne.

Chelocardin is thought to interact at the level of the bacterial membrane; on the other hand, its tetracycline structure suggests an interaction with the A-site of the bacterial ribosome which can interfere with bacterial protein synthesis. Such interaction will be studied by liquid-state NMR of RNA fragments of such site and by docking measurements in the group of Nicola D'Amelio and Catherine Sarazin at UPJV.

Cystobactamids and amidochelocardin, Cathelicidin-BF and SAAP-148 will be tested on relevant clinical isolates, in various combinations and doses. Particular attention will be devoted to opportunistic gram-negative pathogens encountered in France and Germany and listed in the top priority list of WHO. The group of Thierry Naas, at the University Paris Sud, Bicêtre hospital and that of Soeren Gatermann and Niels Pfennigwerth at Ruhr University in Bochum, Germany will share isolates in order to constitute a set fully representing epidemiology in both countries.  Comparative genomics of strains were resistance has been induced will allow us to identify the mutations likely at the origin of the reduced antibiotic susceptibility.

The development of nanogels based on molecularly imprinted polymers (MIPs) provide a mean to deliver both AMPs and antibiotics to the bacterial surface for a synergic action. MIPs are tailor-made synthetic antibody mimics, also referred to as 'plastic antibodies' which can recognize and bind target molecules specifically. They are synthesized by co-polymerizing functional and cross-linking monomers in the presence of a molecular template, resulting in the formation of binding sites with affinities and specificities comparable to those of natural antibodies. Encapsulation of AMPs in MIPs protects peptides from interaction with degrading serum proteases. Furthermore, MIPs can be designed to recognize specific molecules exposed on the bacterial surface, opening the way to delivery in the site of infection. MIPs will be developed in the group of Karsten Haupt, at UTC of Compiegne, France.