A Fluorous Peptide Amphiphile with Potent Antimicrobial Activity for the Treatment of MRSA‐induced Sepsis and Chronic Wound Infection

Abstract

The rising prevalence of global antibiotic resistance evokes the urgent need for novel antimicrobial candidates. Cationic lipopeptides have attracted much attention due to their strong antimicrobial activity, broad‐spectrum and low resistance tendency. Herein, a library of fluoro‐lipopeptide amphiphiles was synthesized by tagging a series of cationic oligopeptides with a fluoroalkyl tail via a disulfide spacer. Among the lipopeptide candidates, R6F bearing six arginine moieties and a fluorous tag shows the highest antibacterial activity, and it exhibits an interesting fluorine effect as compared to the non‐fluorinated lipopeptides. The high antibacterial activity of R6F is attributed to its excellent bacterial membrane permeability, which further disrupts the respiratory chain redox stress and cell wall biosynthesis of the bacteria. By co‐assembling with lipid nanoparticles, R6F showed high therapeutic efficacy and minimal adverse effects in the treatment of MRSA‐induced sepsis and chronic wound infection. This work provides a novel strategy to design highly potent antibacterial peptide amphiphiles for the treatment of drug‐resistant bacterial infections.

Membrane Disruption-Enhanced Photodynamic Therapy against Gram-Negative Bacteria by a Peptide-Photosensitizer Conjugate

“…Taken together, these results indicated that PPC induces the susceptibility of Gram-negative bacteria to phototherapy through membrane disruption, a capability in which conventional PS fails to engage. As a lipopeptide-mimic amphipathic photosensitizer, it is speculated that the hydrophilic ultrashort cation peptide RWRa of PPC first binds to the bacterial membrane due to electrostatic interactions, and then the hydrophobic AIE photosensitizer inserts into the lipid bilayer, eventually causing the physical integrity of the bacterial membrane to be disrupted by PPC. , …”

“…As a lipopeptide-mimic amphipathic photosensitizer, it is speculated that the hydrophilic ultrashort cation peptide RWRa of PPC first binds to the bacterial membrane due to electrostatic interactions, and then the hydrophobic AIE photosensitizer inserts into the lipid bilayer, eventually causing the physical integrity of the bacterial membrane to be disrupted by PPC. 49,50 Given the efficient disruption of the Gram-negative bacterial membrane by PPC for enhanced phototherapeutic antibacterial activity, further elucidation of the interaction sites between PPC and bacterial cell membrane was warranted. Prior to this, critical aggregation concentration (CAC) was measured and the results showed that PPC bears a CAC value of 251 μM, which was much higher than the maximum antibacterial concentration of 32 μM previously used, indicating that PPC behaves as a single molecule when acting with the OM (Figure S19, Supporting Information).…”