Amphipathic β-Strand Mimics as Potential Membrane Disruptive Antibiotics

Abstract

In recent years, there have been increasing numbers of bacterial strains emerging that are resistant to the currently available antibiotics. In the search for new antibiotics, attention has been focused on natural antimicrobial peptides that act by selectively disrupting the membranes of bacterial cells, a mechanism that is thought to be nonconducive to the development of resistance. It is desirable to mimic the structures and activities of these peptides while introducing properties such as resistance to proteolytic degradation, which make molecules more ideal for development as drugs. Described here is the design and synthesis of beta-strand mimetic oligomers based on alternating alpha-amino acids and azacyclohexenone units that segregate cationic lysine and hydrophobic valine side chains on opposite faces of the beta-strand. (1)H NMR dilution studies demonstrated that despite the incorporation of alternating d- and l-amino acids in order to obtain facial amphiphilicity, these oligomers are capable of dimerizing to beta-sheet mimics in a manner similar to the oligomers containing all l-amino acids. The ability of the molecules to disrupt phospholipid vesicles mimicking the membranes of both bacterial and mammalian cells was investigated using a fluorescent dye leakage assay. Several of the oligomers were found to exhibit activity and selectivity for the bacterial over mammalian membranes. Overall, these studies demonstrate the promise of this class of molecules for the development of new potential antibiotics and provide information on the structural features that are important for activity.

Influence of Lysine Nε-Trimethylation and Lipid Composition on the Membrane Activity of the Cecropin A-Melittin Hybrid Peptide CA(1−7)M(2−9)

“…49,55 Our fluorescence results show that N ε -trimethylation slightly decreased the magnitude of partition of the trimethylated peptides to DMPC:DMPG vesicles as compared to the magnitude of partition of the parental peptide and that a different threshold was found for these derivatives than for CA(1-7)M (2)(3)(4)(5)(6)(7)(8)(9) 42 in this model membrane system, which may derive from the different partition constant of the peptides. In fact, CA(1-7)M(2-9) presents a higher partition constant; therefore, a lower peptide concentration is needed to achieve membrane saturation (1:12) as compared to case for the methylated derivatives (1:9).…”

“…[1][2][3][4][5][6][7][8] Thus, vancomycin-resistant enterococci (VRE) and methicillin-resistant Staphylococcus aureus strains (MRSA) have been reported with increasing frequency worldwide. 9 In this crisis scenario, with substantial effort devoted to the discovery of new antibiotic chemotherapeutic resources and strategies, antimicrobial peptides (AMPs) are receiving considerable attention.…”

Antimicrobial peptides: Promising alternatives in the post feeding antibiotic era

“…Some studies have argued that the composition and structure of Gram‐negative and ‐positive cell walls is the basis for the susceptibility of different pathogens to AMPs, such as anionic phospholipids, the lipid A core of LPS of Gram‐negative bacteria and the teichoic and teichuronic acids of Gram‐positive bacteria . Once bound to a microbial surface, peptides cross capsular polysaccharides and other components of the cell wall before they interact with the cytoplasmic membrane in Gram‐positive bacteria . For Gram‐negative bacteria, the initial action of peptides involves the competitive displacement of LPS‐associated divalent cations, for example Mg 2+ and Ca 2+ .…”

Potent Antimicrobial and Antibiofilm Activities of Feleucin-K3 Analogs Modified by α-(4-Pentenyl)-Ala against Multidrug-Resistant Bacteria

“…An explanation for this result might be the structural differences between the bacterial cell walls. AMPs competitively displace the divalent ions (Mg 2+ ) and calcium ions (Ca 2+ ) of the outer membrane by penetrating both the outer and cytoplasmic membranes in Gram-negative bacteria [44]. For Gram-positive bacteria, AMPs can cross peptidoglycan and other components before depolarization of the cytoplasmic membrane [45].…”