Systematically Studying the Optimal Amino Acid Distribution Patterns of the Amphiphilic Structure by Using the Ultrashort Amphiphiles

Abstract

Amphipathicity has traditionally been considered to be essential for the de novo design or systematic optimization of antimicrobial peptides (AMPs). However, the current research methods to study the relationship between amphiphilicity and antimicrobial activity are inappropriate, because the key parameters (hydrophobicity, positive charge, etc.) and secondary structure of AMPs are changed. To systematically and accurately study the effects of amphiphilicity on antimicrobial properties of AMPs, we designed parallel series of AMPs with a different order of amino acids in a sequence composed only of Arg and either Trp (WR series) or Leu (LR series), under conditions in which other vital parameters were fixed. Furthermore, based on the WR and LR peptides that can form stable amphiphilic β-sheet structures in the anionic membrane-mimetic environment, we found that high β-sheet amphipathic was accompanied by strong antimicrobial activity. Of such peptides, W5 ([RW]4W) and L5 ([RL]4L) with a nicely amphipathic β-sheet structure possessed the optimal therapeutic index. W5 and L5 also exhibited high stability in vitro and a potent membrane-disruptive mechanism. These results suggest that the alternate arrangement of hydrophobic and hydrophilic residues to form a stable amphipathic β-sheet structure is an essential factor that significantly affects the antimicrobial properties.

Novel D-form of hybrid peptide (D-AP19) rapidly kills Acinetobacter baumannii while tolerating proteolytic enzymes

“…The secondary structure of peptides in PBS as well as in the membrane mimetic environments (30 mM SDS micelles in PBS and 50% TFE in PBS) was determined by CD spectroscopy. The CD spectra analyses were interpreted in accordance with published data 35 , 36 . As shown in Fig.…”

Highly selective performance of rationally designed antimicrobial peptides based on ponericin-W1

“…At11 and At12 were obtained by introducing two hydrophobic amino acids in the hydrophilic region to make imperfect amphiphilicity. 51…”

“…At11 and At12 were obtained by introducing two hydrophobic amino acids in the hydrophilic region to make imperfect amphiphilicity. 51 Table 1 lists the twelve peptide sequences and their fundamental properties. All peptides contain an overall positive charge but different numbers of net charges and different hydrophobicities as determined by their retention times in RP-HPLC.…”

“…− ), P. aeruginosa (G − ), S. aureus (G + ), and E. faecalis (G + ) a Therapeutic index (TI) was calculated as Minimum Hymolytic Concentration that cause 10% of hemolysis of hRBCs (MHC 10 )/MIC of E. coli or S. aureus. In cases where MHC 10 or MIC was beyond the experimental concentrations, a double concentration of the highest concentration studied was used 51. Biomaterials Science Paper of At3, At5, At8 and At10 was 6.2 μM; for S. aureus, the MBC of At3, At5 and At10 was 25 μM, and the MBC of At8 was 50 μM.…”

Nanostructured Antimicrobial Peptides: Crucial Steps of Overcoming the Bottleneck for Clinics

“…More importantly, Spohn et al found that resistance levels induced by AMP controls were significantly lower than the resistance levels evoked by antibiotic controls (Spohn et al, 2019). These advantages further indicated the potential of AMPs as substitution of antibiotics (Yang et al, 2019;He et al, 2020). Mechanistically, the stereotypical mechanism of AMP action includes the following three steps, largely preventing the occurrence of bacterial resistance: First, the cationic of AMPs exerts a binding process with the negatively charged surfaces of Gram-negative (outer membrane) or Gram-positive (cell wall) bacteria (Figures 1A,B).…”