Polymyxin B‐Triggered Assembly of Peptide Hydrogels for Localized and Sustained Release of Combined Antimicrobial Therapy

Abstract

Repurposing old antibiotics into more effective and safer formulations is an emergent approach to tackle the growing threat of antimicrobial resistance. Herein, a peptide hydrogel is reported for the localized and sustained release of polymyxin B (PMB), a decade-old antibiotic with increasing clinical utility for treating multidrug-resistant Gram-negative bacterial infections. The hydrogel is assembled by additing PMB solution into a rationally designed peptide amphiphile (PA) solution and its mechanical properties can be adjusted through the addition of counterions, envisioning its application in diverse infection scenarios. Sustained release of PMB from the hydrogel over a 5-day period and prolonged antimicrobial activities against Gram-negative bacteria are observed. The localized release of active PMB from the hydrogel is shown to be effective in vivo for treating Pseudomonas aeruginosa infection in the Galleria mellonella burn wound infection model, dramatically reducing the mortality from 93% to 13%. Complementary antimicrobial activity against Gram-positive Staphylococcus aureus and enhanced antimicrobial effect against the Gram-negative Acinetobacter baumannii are observed when an additional antibiotic fusidic acid is incorporated into the hydrogen network. These results demonstrate the potential of the PMB-triggered PA hydrogel as a versatile platform for the localized and sustained delivery of combined antimicrobial therapies.

Gram-selective antibacterial peptide hydrogels

“…[52][53][54][55][56] Excellent antimicrobial activities have been achieved by hydrogels selfassembled by AMPs without loading them with additional antimicrobial drugs. [57][58][59][60] However, the AMP hydrogels that have been developed so far have focused mostly on broad-spectrum antibiotics. There is still a lack of AMP hydrogels that can target Gram-positive or Gram-negative bacteria.…”

Peptide Amphiphile Hydrogels Based on Homoternary Cucurbit[8]uril Host-Guest Complexes

“…A more robust stacking between adjacent indole rings of tryptophan residues in G 5 W-PA can account for this tendency to form bundles, which was not observed in G 5 F-PA under the same micromolar concentration regime. The presence of aggregate structures seen in the TEM images of both guest-PAs, from relatively diluted solutions, indicates working conditions above their critical aggregation concentration, which typically falls in the micromolar concentration regime, even for tryptophan-bearing PA molecules of comparable length to G 5 F-PA and G 5 W-PA . , …”

“…A more robust stacking between adjacent indole rings of tryptophan residues in G 5 W-PA can account for this tendency to form bundles, which was not observed in G 5 F-PA under the same micromolar concentration regime. The presence of aggregate structures seen in the TEM images of both guest-PAs, from relatively diluted solutions, indicates working conditions above their critical aggregation concentration, which typically falls in the micromolar concentration regime, even for tryptophan-bearing PA molecules of comparable length to G 5 F-PA and G 5 W-PA. 45,46 Negatively charged PA molecules analog to E 3 -PA (therefore, analog to G 5 F-PA and G 5 W-PA as well) offer the possibility to access hierarchical nanofiber ordering levels via a thermal process (as detailed in the Experimental Section). Such process renders long-axis nanofibers out of a randomly ordered fiber array in solution, 47 and this process is known to externally expose the amino acid cap and to aggregate internally the palmitoyl tail by an entropy-driven dehydration-rehydration process.…”

Hybrid Nanoparticles and Composite Hydrogel Systems for Delivery of Peptide Antibiotics

“…A release of 60% of the PMX B was observed within 6 h for the antibiotic-loaded hydrogel, whereas the release was only half that value for the composite material for the same time. A comparable rate of PMX B release has also been reported recently by Shi at al., who investigated hydrogels from self-assembling peptide amphiphiles containing negatively charged carboxyl groups and loaded with PMX B [ 46 ]. In particular, the release of 60–80% PMX B after 60 h was documented by those authors.…”