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.