Small Amphiphilic Peptides: Activity Against a Broad Range of Drug-Resistant Bacteria and Structural Insight into Membranolytic Properties

Abstract

We report the synthesis and antibacterial activities of a series of amphiphilic membrane-active peptides composed, in part, of various nongenetically coded hydrophobic amino acids. The lead cyclic peptides, 8C and 9C, showed broad-spectrum activity against drug-resistant Gram-positive (minimum inhibitory concentration (MIC) = 1.5−6.2 μg/mL) and Gram-negative (MIC = 12.5−25 μg/ mL) bacteria. The cytotoxicity study showed the predominant lethal action of the peptides against bacteria as compared with mammalian cells. A plasma stability study revealed approximately 2-fold higher stability of lead cyclic peptides as compared to their linear counterparts after 24 h of incubation. A calcein dye leakage experiment revealed the membranolytic effect of the cyclic peptides. Nuclear magnetic resonance spectroscopy and molecular dynamics simulation studies of the interaction of the peptides with the phospholipid bilayer provided a solid structural basis to explain the membranolytic action of the peptides with atomistic details. These results highlight the potential of newly designed amphiphilic peptides as the next generation of peptide-based antibiotics.

Synthesis and Antibacterial Activity Evaluation of Biphenyl and Dibenzofuran Derivatives as Potential Antimicrobial Agents against Antibiotic-Resistant Bacteria

“…Antibacterial activity assays indicated that most of Compound 6 exhibited significant antibacterial activities against antibiotic-resistant Gram-positive strains but no obvious effects on Gram-negative strains, which demonstrated that these as-synthesized biphenyl and dibenzofuran derivatives have certain selectivity. The MIC values to MRSA of Compounds 6i and 6m were, respectively, 6.25 and 3,13 μg/mL, which are comparable to values reported in the literature [ 39 , 46 ]. On the other hand, the MIC value to MREF of Compound 6l was 6.25 μg/mL, which indicates greater inhibitory activity than that of 4-methoxy-1-(methylthio)dibenzo[ b,d ]furan-2,3-diol (MIC = 12.5 μg/mL), reported by Gao [ 39 ].…”

Membrane-Active Cyclic Amphiphilic Peptides: Broad-Spectrum Antibacterial Activity Alone and in Combination with Antibiotics

“…Thus, it seems that as the hydrophobic bulk increases, the ability of the peptide to discriminate between the anionic bacterial surface and the zwitterionic mammalian membrane decreases. These outcomes are in agreement with many previous reports, 96,97 including ours. Furthermore, we calculated the therapeutic index for MRSA cells by dividing HC 50 values with the MICs against MRSA (Table 1).…”

Structure-Based Rational Design of Small α-Helical Peptides with Broad-Spectrum Activity against Multidrug-Resistant Pathogens

“…A spherical cutoff function (12 Å) and the particle mesh Ewald (PME) algorithm (with a 12 Å cutoff) were used to treat van der Waals and electrostatic interactions, respectively. The preparation and production of the MD stages were the same for all peptides and described elsewhere . Finally, MD production runs (duration at least 200 ns each) were conducted in an NPT ensemble at a semi-isotropic pressure and a constant temperature of 310 K with an integration step of 2 fs.…”

“…Many reports, including ours, 18 previously identified that four cationic and three hydrophobic residues are required in a peptide for antimicrobial activity and selectivity toward the bacterial membrane. Accordingly, in the initial set of heptameric peptides 1a−e, considering the pivotal role of net charge/hydrophobic ratio, 5 we used four cationic (Arg) and three hydrophobic (Trp) residues (peptides 1a−e, Table 1).…”

“…The preparation and production of the MD stages were the same for all peptides and described elsewhere. 18 Finally, MD production runs (duration at least 200 ns each) were conducted in an NPT ensemble at a semi-isotropic pressure and a constant temperature of 310 K with an integration step of 2 fs. 5.14.3.…”