Antibiotic resistance is a daunting challenge for public health systems worldwide. A major goal to fight resistant bacteria involves the design, discovery and development of new antibiotics, particularly against multi-drug-resistant strains. Currently, there is renewed interest in polymyxins, an old class of antimicrobial cyclic lipopeptides, highly potent against therapeutically relevant Gramnegative bacteria. Polymyxins are now used as last resort antibiotics in hospitals because of their nephrotoxicity and neurotoxicity that requires careful monitoring of the patient. Our group has embarked on a project to design and develop new polymyxins devoid of toxicity problems using a versatile and chemically accessible scaffold structure [1,2]. Compounds show excellent activity against Gram-negative bacteria. Synergistic and antibiofilm activities have also been recently described in combination with imipenem [3]. Herein, the latest results of our recently designed polymyxin analogs will be presented. Acknowledgments:The research was supported by the University of Barcelona, Fundació Bosch i Gimpera, Xarxa de Referència en Biotecnologia, 2016LLAVO0018 grant (Generalitat de Catalunya) and the European Institute of Innovation and Technology (EIT Health). The authors are members of the ENABLE (European Gramnegative Antibacterial Engine) consortium (IMI-ND4BB, http://www.imi.europa.eu/projects-results/projectfactsheets/enable).