Antibacterial and Anti-Inflammatory Activity of an Antimicrobial Peptide Synthesized with D Amino Acids.

Jlenia Brunetti,Veronica Carnicelli,Lara Mosconi,Chiara Falciani,Laura Cresti,Alessandro Pini,Loredana Cristiano,Luisa Bracci,Anna Rita Lizzi,Gian Maria Rossolini,Antonio Di Giulio,Giovanni Cappello,Alessia Ponzi,Simona Pollini

doi:10.3390/antibiotics9120840

Abstract

The peptide SET-M33 is a molecule synthesized in tetra-branched form which is being developed as a new antibiotic against Gram-negative bacteria. Its isomeric form with D amino acids instead of the L version (SET-M33D) is also able to kill Gram-positive bacteria because of its higher resistance to bacterial proteases (Falciani et al., PLoS ONE, 2012, 7, e46259). Here we report the strong in vitro activity of SET-M33D (MIC range 0.7–6.0 µM) against multiresistant pathogens of clinical interest, including Gram-positives Staphylococcus aureus, Staphylococcus saprophyticus, and Enterococcus faecalis, and various Gram-negative enterobacteriaceae. SET-M33D antibacterial activity is also confirmed in vivo against a MRSA strain of S. aureus with doses perfectly compatible with clinical use (5 and 2.5 mg/Kg). Moreover, SET-M33D strongly neutralized lipopolysaccharide (LPS) and lipoteichoic acid (LTA), thus exerting a strong anti-inflammatory effect, reducing expression of cytokines, enzymes, and transcription factors (TNF-α, IL6, COX-2, KC, MIP-1, IP10, iNOS, NF-κB) involved in the onset and evolution of the inflammatory process. These results, along with in vitro and in vivo toxicity data and the low frequency of resistance selection reported here, make SET-M33D a strong candidate for the development of a new broad spectrum antibiotic.

Highlights

In recent years, the general misuse of traditional antibiotics has led to a rise in antimicrobial resistance
They they can can play play aa very very important important role role in in the the difficult difficult fight fightagainst against bacteria because they are often active against bacteria resistant to traditional antibiotics, and may bacteria because they are often active against bacteria resistant to traditional antibiotics, and maynot not lead leadto toselection selectionof ofresistant resistantbacteria bacteria[29,30]
This study is a further development of SET-M33D as an active drug in eradicating Gram-negative and Gram-positive bacteria

Summary

Introduction

The general misuse of traditional antibiotics has led to a rise in antimicrobial resistance. D-amino acids), β-peptides or peptoids (N-substituted be an interesting class of molecules because they combine antimicrobial activity with low resistance glycines) [6,7], or by cyclization. Which Inhave a peptidyl corethe of problem radially branched residues onto which peptide peptide properties and selectivity, researchers have changed peptide structure in various ways, such as by sequences can be added, were synthesized [8]. These peptides have strong resistance to proteolysis incorporating unnatural amino suitable acids (e.g., which makes them for use in vivo [9,10,11].β-peptides or peptoids (N-substituted glycines)

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