An antimicrobial molecule mitigates signs of sepsis in vivo and eradicates infections from lung tissue

Abstract

The peptide sequence KKIRVRLSA was synthesized in a dimeric structure (SET-M33DIM) and evaluated as a candidate drug for infections due to multidrug-resistant (MDR) Gram-negative pathogens. SET-M33DIM showed significant antibacterial activity against MDR strains of Klebsiella pneumoniae, Acinetobacter baumannii, and Escherichia coli (Minimal Inhibitory Concentration [MICs], 1.5-11 µM), and less activity against Pseudomonas aeruginosa (MICs, 11-22 µM). It showed very low toxicity in vitro, ex vivo, and in vivo; in cytotoxicity tests, its EC 50 was as much as 22 times better than that of SET-M33, a peptide with the same amino-acid sequence, but synthesized in tetra-branched form (638 vs 28 µM). In in vivo and ex vivo experiments, SET-M33DIM cleared P. aeruginosa infection, significantly reducing signs of sepsis in animals, and restoring cell viability in lung tissue after bacterial challenge. It also quelled inflammation triggered by LPS and live bacterial cells, inhibiting expression of inflammatory mediators in lung tissue, cultured macrophages, and bronchial cells from a cystic fibrosis patient. K E Y W O R D S antibacterial agents, antibiotic resistance, antimicrobial peptides, drug development | 193 QUERCINI Et al.

Safety evaluations of a synthetic antimicrobial peptide administered intravenously in rats and dogs

“…The peptide SET-M33 is a synthetic molecule under study for the development of a new antibacterial drug. SET-M33 and some of its back-up molecules have already been reported for antibacterial efficacy in different infections and inflammation models in vivo and ex vivo, including sepsis 22 , 24 , 26 , pneumonia 24 , 27 , 29 , 39 and skin infections 24 . As a novel drug to administer intravenously, SET-M33 has entered a preclinical development phase that includes scale up of production, adsorption, excretion 24 and finally toxicity, the subject of the present report.…”

“…Its mode of action features a two-step mechanism: (1) high affinity binding to LPS 24 and (2) disruption of bacterial membranes 25 . Data on similar forms of the peptide, such as SET-M33D 26 , SET-M33DIM 27 , SET-M33Peg 28 and SET-M33 encapsulated in dextran nanoparticles 29 , has been reported with in vivo activity as well. The peptide SET-M33 has completed preclinical development as a new antibacterial agent against major Gram-negative pathogens.…”

Esc peptides as novel potentiators of defective cystic fibrosis transmembrane conductance regulator: an unprecedented property of antimicrobial peptides

“…In recent years, the employment of peptides as candidates for clinical translation has gained a raising interest, mainly due to their high specificity, safety, and tolerability [21,56,57]. Nowadays, there are more than 50 commercially available peptide-based medicines [58], while hundreds of them are under preclinical and clinical experimentation for the development of new drugs, including those aimed at treating respiratory infections, either following intravenous injection (i.e., POL7080) or inhalation.…”

“…This latter is the most advantageous administration route to maximize drug efficacy for treatment of lung infections and to reduce side effects of drugs, compared to oral and/or i.v. injection [ 57 , 59 ]. Peptide-based drugs marketed as inhaled medications for CF, upon nebulization, encompass the recombinant version of the human DNaseI (Pulmozyme®) to decrease mucus viscosity [ 60 ].…”

Inhalable Polymeric Nanoparticles for Pulmonary Delivery of Antimicrobial Peptide SET-M33: Antibacterial Activity and Toxicity In Vitro and In Vivo

“…Its tetra-branched form confers high resistance to protease and peptidase activities, making these molecules good candidates for in vivo use [ 9 , 10 , 11 , 12 , 13 , 14 ]. The peptide is active against a panel of clinically prominent Gram-negative bacteria, including many clinical isolates of Escherichia coli , Acinetobacter baumannii , Klebsiella pneumoniae , Pseudomonas aeruginosa and other Enterobacteriaceae [ 15 , 16 ].…”