Esculentin-1a derivatives as new antipseudomonal agents: limited induction of resistance and inhibition of biofilm formation

Cationic α-helical antimicrobial peptides (AMPs) hold promise as new therapeutics thanks to their broad spectrum of activity and membrane-perturbing mechanism of action. These features make them interesting compounds compared to conventional antibiotics that easily induce microorganisms to acquire resistance to them. One of these microbes is the opportunist Gram-negative bacterium Pseudomonas aeruginosa. It colonizes abiotic surfaces and tissues growing in a more resistant form, named biofilm. Recently, two derivatives of the AMP esculentin-1a, e.g. Esc(1-21) and its diastereomer Esc(1-21)-1c [Esc-peptides] were characterized for their activity against both planktonic and biofilm forms of P. aeruginosa [1,2]. The ability of these peptides to limit the onset of microbial resistance was evaluated by exposing Pseudomonas strains to repeated treatments with different concentrations of each peptide and the results were compared to conventional antibiotics. Interestingly, while after 15 cycles of drug exposure, the minimal growth inhibitory concentrations (MICs) of ciprofloxacin, aztreonam, colistin and tobramycin were found to be 8 to 128-fold higher than the initial ones, the MICs of Esc-peptides did not change. In addition, while sub-MIC levels of antibiotics stimulated Pseudomonas biofilm formation, the D-amino acid containing Esc(1-21)-1c inhibited its formation. This could be explained by the peptide’ binding to the bacterial signaling nucleotide ppGpp, with consequent reduction in the expression of key genes involved in bacterial virulence. Overall, these results suggest Esc-peptides, particularly Esc(1-21)-1c, as promising candidates for the development of new antimicrobials. [1] Luca V. et al, Cell Mol Life Sci. 2013 Aug;70(15):2773-86; [2] Di Grazia A. et al, Amino Acids. 2015 Dec;47(12):2505-19; Acknowledgments: This work was supported by grants from Sapienza University and from the Italian Cystic Fibrosis Foundation (project FFC 15/2017)