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Background The massive use of antibiotics has led to the selection of resistant bacterial strains that are difficult to eradicate. Among these, Pseudomonas aeruginosa most frequently colonizes and infects the airways of cystic fibrosis patients. Cationic Antimicrobial Peptides (AMPs) represent interesting molecules for the development of new antimicrobial agents. Thanks to their mechanism of action that involves the permeabilization of the bacterial cytoplasmic membrane, the induction of resistance is quite limited. Objective The evaluation of the capability of two frog-skin derived AMPs, i.e. Esc(1-21) and its diastereomer Esc(1-21)-1c, to induce resistance in P. aeruginosa and synergize with aztreonam. Method The induction of resistance was evaluated after 15 cycles of exposure to non-inhibitory growth concentrations of antibiotics and peptides. Subsequently, the Minimal Inhibitory Concentration (MIC) was calculated and compared to that obtained before drug exposure. Furthermore, MICs of AMPs and antibiotics were evaluated in Artificial Sputum Medium (ASM). Finally, the ability of the two peptides to synergize with aztreonam was determined by the checkerboard titration method. Results Pseudomonas aeruginosa acquired resistance to antibiotics, as evidenced by the increased MICs compared to the initial ones (from 8 to 128-fold higher), while no change in MICs was observed after multiple treatments with the Esc-peptides. In addition, both peptides showed significantly lower MICs than aztreonam in ASM. Finally, the diastereomer Esc(1-21)-1c had the ability to synergize with aztreonam in inhibiting growth and in killing Pseudomonas cells. Conclusion Both peptides represent promising candidates for the development of new antipseudomonal compounds, which do not induce resistance.