Antibacterial agents based on the cyclic d,l-α-peptide architecture

Abstract

The rapid emergence of bacterial infections that are resistant to many drugs underscores the need for new therapeutic agents. Here we report that six- and eight-residue cyclic d,l-alpha-peptides act preferentially on Gram-positive and/or Gram-negative bacterial membranes compared to mammalian cells, increase membrane permeability, collapse transmembrane ion potentials, and cause rapid cell death. The effectiveness of this class of materials as selective antibacterial agents is highlighted by the high efficacy observed against lethal methicillin-resistant Staphylococcus aureus infections in mice. Cyclic d,l-alpha-peptides are proteolytically stable, easy to synthesize, and can be derived from a potentially vast membrane-active sequence space. The unique abiotic structure of the cyclic peptides and their quick bactericidal action may also contribute to limit temporal acquirement of drug resistant bacteria. The low molecular weight d,l-alpha-peptides offer an attractive complement to the current arsenal of naturally derived antibiotics, and hold considerable potential in combating a variety of existing and emerging infectious diseases.

The orientation of the antibiotic peptide maculatin 1.1 in DMPG and DMPC lipid bilayers. Support for a pore‐forming mechanism

“…As peptides which form oligomers upon membrane binding (a prerequisite condition for channel formation) do not readily cross the outer membrane of Gram-negative bacteria [10], this also would seem to suggest that the mechanism of action is via formation of a channel. If maculatin were acting via the`carpet' mechanism, one would expect the peptide to possess activity against both Gram-positive and Gram-negative bacteria [30].…”

Structural, Nanomechanical, and Computational Characterization of d,l-Cyclic Peptide Assemblies

“…20 As DLCPs are synthesized via common solid-state peptide synthesis methods 24 , one has the freedom to explore limitless combinations of amino acids and postsynthetic modifications. 25 This versatility has been leveraged to study DLCPs in a variety of applications including structural antibiotics, 26 ion channels, 27 selective ion transporters, 28 and reinforcing agents. 29 Additional research has focused on the fundamental properties of cyclic peptides including the thermodynamics of assembly and the breadth of structural flexibility.…”

Fungal cyclooligomerdepsipeptides: From classical biochemistry to combinatorial biosynthesis

“…Beauvericin (1), enniatins (2), bassianolide (3) and PF1022A (4) and its congeners contain residues with alternating D and L configuration, similar to 6-8-member cyclic D,L-a-peptide antibacterial agents. 10,11 Variations in the amino acid or the hydroxycarboxylic acid positions of the monomers lead to the production of various COD congeners in a given COD producer fungus. COD production in fungi has hitherto been only documented in the Hypocreomycetidae and the Xylariomycetidae, two subclasses of the Sordariomycetes.…”