A Synthetic Antimicrobial Peptidomimetic (LTX 109): Stereochemical Impact on Membrane Disruption

Abstract

LTX 109 is a synthetic antimicrobial peptidomimetic (SAMP) currently in clinical phase II trials for topical treatment of infections of multiresistant bacterial strains. All possible eight stereoisomers of the peptidomimetic have been synthesized and tested for antimicrobial effect, hemolysis, and hydrophobicity, revealing a strong and unusual dependence on the stereochemistry for a molecule proposed to act on a general membrane mechanism. The three-dimensional structures were assessed using nuclear magnetic resonance spectroscopy (NMR) and molecular dynamics (MD) simulations in aqueous solution and in phospholipid bilayers. The solution structures of the most active stereoisomers are perfectly preorganized for insertion into the membrane, whereas the less active isomers need to pay an energy penalty in order to enter the lipid bilayer. This effect is also found to be reinforced by a significantly improved water solubility of the less active isomers due to a guanidyl-π stacking that helps to solvate the hydrophobic surfaces.

In Vitro Activities of LTX-109, a Synthetic Antimicrobial Peptide, against Methicillin-Resistant, Vancomycin-Intermediate, Vancomycin-Resistant, Daptomycin-Nonsusceptible, and Linezolid-Nonsusceptible Staphylococcus aureus

“…LTX-109 (Lytixar; Lytix Biopharma AS, Oslo, Norway) is one such novel SAMP which rapidly kills bacteria via membrane disruption and has not been associated with cross-resistance to other available drugs. LTX-109 has also been shown to have a low propensity for the development of resistance (5,6,8).…”

LTX-109 Is a Novel Agent for Nasal Decolonization of Methicillin-Resistant and -Sensitive Staphylococcus aureus

“…The mechanism of action of LTX-109 represents a new and innovative bactericidal approach via a direct membrane disruption (17,18). The product has been shown not to be affected by cross-resistance to other available drugs and has demonstrated a low propensity for development of resistance (17,18,24). In the present study, a significant reduction of S. aureus CFU was demonstrated already after 2 days, although bacterial recurrence was observed in all but one subject 5 days after the end of treatment.…”

“…LTX-109 is a broad-spectrum, fast-acting bactericidal antimicrobial drug that binds to negatively charged membrane components on the bacterial cell, which is followed by membrane disruption and cell lysis (17,18). Nonclinical and clinical studies have demonstrated that topical application of LTX-109 (1 to 5%) has a good safety profile and a low bioavailability (19).…”

Membrane‐Active Small Molecules: Designs Inspired by Antimicrobial Peptides

“…When the Cterminus of this molecule was capped by an ethylphenylg roup,L TX-109w as obtained, which is undergoing clinical trials (Table 7, Structure 18). [47] Over severaly ears, Bremner et al attempted to mimic the action of vancomycin by designing small cationic cyclic peptoids.…”

“…[47] From the data furnished on the company website, it is apparent that these short cationic peptidomimetics werea blet oa chieve antimicrobial activity against MRSA in am ouse skin infection model with efficacies better than the approved drugs Albataxa nd Fucidin. [3] In fact, they have recently shown the efficacy of LTX-109a sanovel agent for nasal decolonizationo fm ethicillin-resistant and -sensitive S. aureus in humans.…”