In vitro and in vivo efficacy, toxicity, bio-distribution and resistance selection of a novel antibacterial drug candidate

Abstract

A synthetic antimicrobial peptide was identified as a possible candidate for the development of a new antibacterial drug. The peptide, SET-M33L, showed a MIC90 below 1.5 μM and 3 μM for Pseudomonas aeruginosa and Klebsiella pneumoniae, respectively. In in vivo models of P. aeruginosa infections, the peptide and its pegylated form (SET-M33L-PEG) enabled a survival percentage of 60–80% in sepsis and lung infections when injected twice i.v. at 5 mg/Kg, and completely healed skin infections when administered topically. Plasma clearance showed different kinetics for SET-M33L and SET-M33L-PEG, the latter having greater persistence two hours after injection. Bio-distribution in organs did not show significant differences in uptake of the two peptides. Unlike colistin, SET-M33L did not select resistant mutants in bacterial cultures and also proved non genotoxic and to have much lower in vivo toxicity than antimicrobial peptides already used in clinical practice. The characterizations reported here are part of a preclinical development plan that should bring the molecule to clinical trial in the next few years.

Immunomodulatory and Anti-inflammatory Activity in Vitro and in Vivo of a Novel Antimicrobial Candidate

“…SET-M33 has already been reported for its efficacy in killing bacterial pathogens in vitro and in vivo (10). Here we report its in vitro and in vivo activity in modulating cell response to inflammatory stimuli (LPS) from different bacteria of clinical interest and its capacity to promote cell migration.…”

“…The plan is to administer SET-M33 to CF patients by aerosol. After demonstration of its bactericidal activity in vivo by intratracheal inoculation (10), the demonstration of a reduction in major inflammatory cytokines in vivo is of great significance for the treatment of CF patients with this molecule.…”

“…We isolated, optimized, and synthesized a peptide (SET-M33) that shows strong antimicrobial activity in vitro and in vivo against major Gram-negative pathogens (7–10). SET-M33 was synthesized in a branched form (11) for better stability in biological fluids (12–16).…”

“…Preclinical development of SET-M33, currently underway, has already provided information about its therapeutic power in vivo in cases of sepsis, models of skin and lung infections, gene toxicity, acute toxicity in vivo , its propensity to select bacterial resistances, pharmacokinetics, and biodistribution (10). Because SET-M33 is a drug candidate for lung infections in CF, its potential as an anti-inflammatory agent is also of great interest.…”

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

“…[23][24][25][26][27][28] It is a non-natural cationic peptide built in tetra-branched form. [23][24][25][26][27][28] It is a non-natural cationic peptide built in tetra-branched form.…”