A) We emphasise that the participants of the tender set the goals abundantly two years ago, they work together on these plans on a daily basis, and can produce a number of encouraging preliminary results. Due to the scarcity of resources, these results are not systematic: we've worked with few active molecules, few pathogens, and in vivo tests are missing. A successful application would fill this gap. Our work plan has two sub-programmes, which we present, outlining the preliminary results, the plans and the expected breakthrough results. Sub-programme 1 1.1 Testing of antibiotic resistant strains against AMPs (Pál), complete genome sequencing (Kondorosi) and bioinformatics analysis of results (Papp) 1.2 AMP — low-molecule antibiotic combinations (Pál, Papp) 1.3 Synthesis of new building blocks for AMP mimetic foldamers (Fülöp), switching and purification of sequences (Martinek, Tóth), and Biophysical Characterisation (Martinek) 1.4 Testing of AMP mimetic foldamers in vitro and in vivo (Pál, Kondorosi) and Toxicity Tests (Földesi) 2 sub-programme 2.1 Production of SSB-C foldamer analogues (Martins), stabilisation by side chain bridging (Tóth), synthesis of required monomers (Fülöp) and in vitro testing for PPI inhibition. 2.2 SSB-C Mymetics — Structural Characterisation of Reco-WH Interaction (Martinek) 2.3 SSB-C Analogs Optimising Dynamic Covalent Library Method. Cell penetration studies (Martin) 2.4 Real-time in vitro evolutionary studies, antibacterial testing (Pál, Papp), toxicity studies (Göldesi). B) 1. SUB-PROJECT: Antimicrobial peptides AMPs are short peptides with a divergent structure and function that protect the host against various microbial infections. They are found in plants, animals, fungi and are part of a primary system of protection against pathogens. [Nature 2002, 415, 389] Although they have remained effective in evolution, their practical application raises a number of problems, two of which are concentrated on: 1) At present, there is serious debate about the development of resilience against these molecules and, if so, what harmful side effects it may have. [FEMS Microbiol Lett 2012, 330, 81] 2) A further problem prior to clinical use of peptides is that they are sometimes difficult to administer and absorb and may be degraded by human protein-depleting enzymes (proteases). Their in vivo stability is often unsatisfactory. Our preliminary investigations show that these problems can be overcome. Moreover, AMPs are particularly effective against multidrug resistant bacteria. To do this, it is necessary to select AMPs against which resistance is not observed. These molecules are the basis for further development: while retaining the above favourable structural and functional properties, we design so-called peptidomimetic foldamer molecules. Our aim is to demonstrate that the combination of these peptidomimetics with antibiotics is exceptionally effective in combating resistance. Preliminary results and plans: The Achilles heel of multidrug resistant bacteria can be attacked by AMPs. Detailed genetic, biochemical, phenotipus tests and genome-level expression tests of the groups led by Csaba Pál, Balázs Papp and Éva Kondorosi confirmed that the membrane structure, rigidity and membrane protein composition of resistant bacteria often changed significantly. [NAT Commun 2014, 5, 4352; Mol Syst Biol 2013, 9, 700] Since most AMP’s primary target is the bacterial membrane, it has been suggested that antibiotic resistance also affects susceptibility to AMP. The result was unexpected and very interesting. 90 % of multidrug resistant strains have become hypersensitivity to multiple AMPs: compared to baseline control strains, the sensitivity of these strains generally increased by two to three times. This shows that there is a serious cost of developing antibiotic resistance, which can potentially be exploited by co-administration of antibiotics and AMPs. Effective AMP antibiotic combination therapy. In the next step, the partners focus on two key issues. Are there any AMPs that are co-administered with antibiotics (a) inhibit de novo resistance in vitro and (b) effectively kill multidrug resistant bacteria. Their studies focus on two AMPs: the NCR335 peptide and the selfinine peptide family to PGLA. For both peptides, 90-100 % of multidrug resistant strains remained highly sensitive to them. Preliminary results: a) Tetracycline and ciprofloxacin resistant bacteria have become more sensitive to these agents by adding PGLA to the antibiotic. The impact is dramatic in several cases: antibiotic susceptibility increases 10-50 times with a very low (subinhibitory) PGLA dose.