Small AntiMicrobial Peptide with In Vivo Activity Against Sepsis

Abstract

Antimicrobial peptides (AMPs) are considered as potential therapeutic sources of future antibiotics because of their broad-spectrum activities and alternative mechanisms of action compared to conventional antibiotics. Although AMPs present considerable advantages over conventional antibiotics, their clinical and commercial development still have some limitations, because of their potential toxicity, susceptibility to proteases, and high cost of production. To overcome these drawbacks, the use of peptides mimics is anticipated to avoid the proteolysis, while the identification of minimalist peptide sequences retaining antimicrobial activities could bring a solution for the cost issue. We describe here new polycationic -amino acids combining these two properties, that we used to design small dipeptides that appeared to be active against Gram-positive and Gram-negative bacteria, selective against prokaryotic versus mammalian cells, and highly stable in human plasma. Moreover, the in vivo data activity obtained in septic mice reveals that the bacterial killing effect allows the control of the infection and increases the survival rate of cecal ligature and puncture (CLP)-treated mice.

In vitro activity of antimicrobial peptide CDP-B11 alone and in combination with colistin against colistin-resistant and multidrug-resistant Escherichia coli

“…Peptide DGL13K was shown to treat burns infected with Pseudomonas aeruginosa in mice without toxic effects 20 . Similarly, “Peptide 11”, a non-natural peptide, described by Boullet et al showed approximately 50% survival rate against septic in mice compared to a 0% survival rate in the control population 21 . These peptides show proof of concept that AMPs, either natural or non-natural can work in vivo.…”

Эволюционное Развитие И Структурное Разнообразие Природных Антимикробных Пептидов, Пептидомиметиков И Катионных Амфифилов На Основе Аминокислот

“…5) [56]. Трикатионные производные β-аминокислот с остатками L-орнитина/L-аргинина в полярной части активны против грамположительных и грамотрицательных бактерий, стабильны в плазме человека, обладают селективностью против прокариотов и позволяют контролировать инфекцию, увеличивая выживаемость мышей с модельным сепсисом [57].…”

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes–5

“…Membrane-active AMPs are appealing due to their low propensity for inducing the development of resistance but still present drawbacks such as toxicity, susceptibility to proteases, and manufacturing costs. Inspired by Svendsen and co-workers [14], who defined the pharmacophore of AMPs as two cationic charges and two bulky hydrophobic aromatic units, Boullet et al [15], with the idea of keeping the AMPs simple and stable, synthetized new β 2,2 - and β 3,3 -bis- homo -ornithine/arginine peptides. This series of cationic peptides combined with the supertryptophan residue furnished AMPs with MIC values in the range of 2 to 16 µg/mL, active against both Gram-positive and Gram-negative bacteria.…”