Cyclization Improves Membrane Permeation by Antimicrobial Peptoids

Abstract

The peptidomimetic approach has emerged as a powerful tool for overcoming the inherent limitations of natural antimicrobial peptides, where the therapeutic potential can be improved by increasing the selectivity and bioavailability. Restraining the conformational flexibility of a molecule may reduce the entropy loss upon its binding to the membrane. Experimental findings demonstrate that the cyclization of linear antimicrobial peptoids increases their bactericidal activity against Staphylococcus aureus while maintaining high hemolytic concentrations. Surface X-ray scattering shows that macrocyclic peptoids intercalate into Langmuir monolayers of anionic lipids with greater efficacy than for their linear analogues. It is suggested that cyclization may increase peptoid activity by allowing the macrocycle to better penetrate the bacterial cell membrane.

Peptoid drug discovery and optimization via surface X‐ray scattering

“…Traversing the entirety of bacterial membrane is likely not the primary mode of action by antimicrobial peptoids with high selectivity (Figure B). In tandem to the previous works these results allow for proposing formation of toroidal pores as a membrane disruptive mechanism by macrocyclic peptoids …”

“…Comparative analysis of linear and macrocyclic peptoids with identical monomer composition reveals superior in vitro efficacy by the latter ones against Gram‐positive and Gram‐negative bacteria . The membrane integrity of methicillin‐resistant Staphylococcus aureus (MRSA) is compromised, with extensive pore formation observed at the macro‐scale level, yet the specific barrel‐stave or toroidal pore mechanisms cannot be identified. XRR on DPPG and Kdo 2 ‐lipid A monolayers provides a first‐time evidence of the molecular‐level changes in lipid arrangement by macrocyclic peptoids that may explain their antimicrobial activities .…”

“…The membrane integrity of methicillin‐resistant Staphylococcus aureus (MRSA) is compromised, with extensive pore formation observed at the macro‐scale level, yet the specific barrel‐stave or toroidal pore mechanisms cannot be identified. XRR on DPPG and Kdo 2 ‐lipid A monolayers provides a first‐time evidence of the molecular‐level changes in lipid arrangement by macrocyclic peptoids that may explain their antimicrobial activities . The additional electron density contributed by peptoids of linear structure is evenly distributed along the surface normal (Figure ).…”

Basic Design Elements for Tunable Cation Transport Using Picolinic‐Acid‐Incorporated Tetrapeptides

“…Similar effects have been observed in nature wherein minor changes in the number of oxygen atoms within the pore brought about by protein conformation has pronounced effects on ion‐selectivity . The importance of the constrained conformation can also be realized from reports which show that a more constrained cyclic structure gets more efficiently inserted into membrane bilayers . Therefore, a dimeric pore as shown in Figure b is proposed for these molecules.…”

1,2,3‐Triazolium‐Based Cationic Amphipathic Peptoid Oligomers Mimicking Antimicrobial Helical Peptides

“…As for AMPs, studies have provided evidence that amphipathic cationic peptoids act by bacterial membrane disruption; however, additional modes of action are not excluded . Changes in membrane morphology of S. aureus bacteria upon treatment with dodecamer 7 , the longest peptoid from the A series and the short hexamer 3 from the B series, were visualized by scanning electron microscopy (SEM; Figure ).…”