New Short Cationic Antibacterial Peptides. Synthesis, biological activity and mechanism of action

GARRO, ADRIANA; RICCI, MARIA; VEGA HISSI, ESTEBAN; ZURITA, ADOLFO; FÜLÖP, LIVIA; BEKE-SOMFAI, TAMAS ; ENRIZ, RICARDO DANIEL

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Congreso; Biofísica en tiempos de COVID-19 SAB 2020; 2020

Sociedad Argentina de BiofísicaResearch Centre for Natural Sciences, Institute of Materials and Environmental Chemistry, H-1117

We report a theoretical and experimental study on a new series of antibacterial peptideswith small-size. Synthesis and bioassays are reported here. In addition, differentphysicochemical parameters that modulate antimicrobial activity (charge, secondarystructure, hydrophobicity, amphipathicity and polarity) have been evaluated. Moleculardynamic simulations were also performed for these peptides. The biophysicalcharacterization of peptides was carried out by using different techniques, such ascircular dichroism (CD), linear dichroism (LD), infrared spectroscopy (IR), dynamic lightscattering (DLS) and TEM study employing model systems (liposomes) for mammalianand bacterial membranes, respectively. Results obtained in this work allow us to drawimportant conclusions on two different aspects:I) Our results (theoretical and experimental) indicate that small-sized peptides have aparticular mechanism of action that is different from that of large peptides. These resultsare a support for a four-step mechanism previously proposed (1). It is important toremark that in this mechanism, being able to reach a threshold concentration of peptidesand thus, a non-monomeric state, is a key step for a successful process. Thus, thismechanism explains the importance of maintaining a delicate balance between affinityfor the bilayer surface, a low peptide-peptide repulsion (in order to reach the thresholdconcentration) and an acceptable tendency to penetrate into the bilayer.II) Previously, it has been proposed as ?pharmacophore? or minimum structuralrequirement for these short peptides, a sequence with at least 3 R and 3 W (2). Ourresults are in line with this proposal. An important information obtained from our study isthat for such 9 amino acid long peptides, a net charge of +4 is the adequate to produceantibacterial activity. The information obtained here is very important for the design ofnew antibacterial peptides with these structural characteristics.