Selective Permeabilization of Gram-Negative Bacterial Membranes Using Multivalent Peptide Constructs for Antibiotic...

Area of Science:

• Microbiology
• Drug Delivery
• Antimicrobial Resistance

Background:

• Gram-negative bacteria possess drug-impermeable membranes, hindering antibiotic access to intracellular targets.
• The diminishing antibiotic arsenal necessitates strategies to enhance drug delivery into these pathogens.

Purpose of the Study:

• To engineer macromolecular potentiators for improved intracellular antibiotic delivery in Gram-negative bacteria.
• To assess the efficacy of these potentiators in overcoming bacterial membrane barriers and enhancing antibiotic activity.

Main Methods:

• Synthesis of WD40 potentiators by grafting WLBU2 antimicrobial peptides onto a dextran scaffold.
• Evaluation of WD40-mediated drug uptake in *P. aeruginosa* and other clinical strains.
• Determination of minimum inhibitory concentrations (MICs) for various antibiotics potentiated by WD40.

Main Results:

• WD40 facilitated intracellular drug uptake in *P. aeruginosa*, unlike unmodified WLBU2.
• WD40 reduced antibiotic MICs by up to three orders of magnitude, with greatest potentiation for hydrophobic and complex antibiotics.
• Potentiation was observed across multiple clinical strains, including sensitization of resistant strains to rifampin.

Conclusions:

• Engineered macromolecular potentiators (WD40) effectively enhance antibiotic permeation across Gram-negative bacterial membranes.
• This strategy broadens the utility of existing antibiotics and offers potential for combating drug-resistant Gram-negative infections.
• WD40 represents a promising approach to revitalize the antibiotic arsenal against challenging pathogens.