(69e) Synergistic Interactions of Nanonet Forming Peptides to Combat Resistance

Multidrug resistant Gram-negative pathogens present an increasingly critical healthcare threat. While the intracellular therapeutic targets of multiple antibiotic classes are well conserved between Gram-positive and Gram-negative bacteria, the outer membrane of the latter is highly efficient at denying entry to xenobiotics, thus impeding drug discovery efforts. Our group previously designed a library of synthetic beta-hairpin antimicrobial peptides (AMPs). Some of the potent candidates displayed the unique ability to form on-demand bacteria-trapping nanonets. We hypothesized that mechanical damage to the outer membranes from entrapment by the nanonets would facilitate the entry of putative Gram-positive-selective antibiotics, thus expanding their activity spectrum against Gram-negative pathogens. We successfully demonstrated synergistic interactions between our peptides and a panel of clinically relevant antibiotic classes, with clear distinction in the synergy profile between non-fibrillating and fibrillating peptides. The inclusion of fibrillating peptides at sub-inhibitory concentrations strongly delayed resistance development against the antibiotic, whereas non-fibrillating peptides did not. Findings of strain-specific synergy profiles led us to postulate that intracellular mechanisms were involved. Overall, this work demonstrated the potential of nanonets-forming AMPs as an adjuvant for unlocking antibiotic activity against multidrug resistant Gram-negative bacteria.