Role of Amphiphilicity in the Design of Synthetic Mimics of Antimicrobial Peptides with Gram-Negative Activity

Two new series of aryl SMAMPs (synthetic mimics of antimicrobial peptides) with facially amphiphilic (FA) and disrupted amphiphilic (DA) topologies were designed and synthesized to directly assess the role of amphiphilicity on their antimicrobial activity against Gram-positive and Gram-negative bacteria in closely related structures. The FA SMAMPs displayed broad spectrum antimicrobial activity against both Gram-positive <i>S. aureus</i> and Gram-negative <i>E. coli</i>, whereas the DA SMAMPs, which contained a polar amide bond in between the hydrophobic moieties, only exhibited activity toward <i>S. aureus</i> with increasing hydrophobicity. The integy moment (IW) was used to quantify the amphiphilicity of the SMAMPs and confirmed that it is critical for the design of SMAMPs with Gram-negative activity

Expedient Synthesis of SMAMPs via Click Chemistry

A novel series of synthetic mimics of antimicrobial peptides (SMAMPs) containing triazole linkers were assembled using click chemistry. While only moderately active in buffer alone, an increase in antimicrobial activity against <i>Staphylococcus aureus</i> and <i>Escherichia coli</i> was observed when these SMAMPs were administered in the presence of mouse serum. One compound had minimum inhibitory concentrations (MICs) of 0.39 μg/mL and 6.25 μg/mL, respectively, and an HC₅₀ of 693 μg/mL. These values compared favorably to peptide-based antimicrobials. A correlation between the net positive charge and SMAMP antimicrobial activity was observed. The triazole linker, an amide surrogate, was found to provide better antimicrobial activity against both <i>S. aureus</i> and <i>E. coli</i> when compared to other analogues

Nanostructured Block-Random Copolymers with Tunable Magnetic Properties

It was recently shown that block copolymers (BCPs) produced room-temperature ferromagnetic materials (RTFMs) due to their nanoscopic ordering and the cylindrical phase yielded the highest coercivity. Here, a series of metal-containing block-random copolymers composed of an alkyl-functionalized homo block (C₁₆) and a random block of cobalt complex- (Co) and ferrocene-functionalized (Fe) units was synthesized via ring-opening metathesis polymerization. Taking advantage of the block-random architecture, the influence of dipolar interactions on the magnetic properties of these nanostructured BCP materials was studied by varying the molar ratio of the Co units to the Fe units, while maintaining the cylindrical phase-separated morphology. DC magnetic measurements, including magnetization versus field, zero-field-cooled, and field-cooled, as well as AC susceptibility measurements showed that the magnetic properties of the nanostructured BCP materials could be easily tuned by diluting the cobalt density with Fe units in the cylindrical domains. Decreasing the cobalt density weakened the dipolar interactions of the cobalt nanoparticles, leading to the transition from a room temperature ferromagnetic (RTF) to a superparamagnetic material. These results confirmed that dipolar interactions of the cobalt nanoparticles within the phase-separated domains were responsible for the RTF properties of the nanostructured BCP materials

Synthetic Mimics of Antimicrobial Peptides with Immunomodulatory Responses

A new series of aryl-based synthetic mimics of antimicrobial peptides (SMAMPs) with antimicrobial activity and selectivity have been developed via systematic tuning of the aromatic groups and charge. The addition of a pendant aromatic group improved the antimicrobial activity against Gram-negative bacteria, while the addition of charge improved the selectivity. SMAMP <b>4</b> with six charges and a naphthalene central ring demonstrated a selectivity of 200 against both Staphylococcus aureus and Escherichia coli, compared with a selectivity of 8 for the peptide <b>MSI-78</b>. In addition to the direct antimicrobial activity, SMAMP <b>4</b> exhibited specific immunomodulatory activities in macrophages both in the presence and in the absence of lipopolysaccharide, a TLR agonist. SMAMP <b>4</b> also induced the production of a neutrophil chemoattractant, murine KC, in mouse primary cells. This is the first nonpeptidic SMAMP demonstrating both good antimicrobial and immunomodulatory activities

Synthetic Mimics of Antimicrobial Peptides from Triaryl Scaffolds

In this report, we describe the synthesis of a new series of small amphiphilic aromatic compounds that mimic the essential properties of cationic antimicrobial peptides using Suzuki-Miyaura coupling. The new design allowed the easy tuning of the conformational restriction, controlled by introduction of intramolecular hydrogen bonds, and the overall hydrophobicity by modifications to the central ring and the side chains. This approach allowed us to better understand the influence of these features on the antimicrobial. activity and selectivity. We found that the overall hydrophobicity had a more significant impact on antimicrobial and hemolytic activity than the conformational stiffness. A novel compound was discovered which has MICs of 0.78 mu g/mL against S. Aureus and 6.25 mu g/mL against E. Coli, similar to the well-known antimicrobial peptide, MSI-78