Unnatural Amino‐Acid‐Based Star‐Shaped Poly(l‐Ornithine)s as Emerging Long‐Term and Biofilm‐Disrupting Antimicrobial Peptides to Treat Pseudomonas aeruginosa‐Infected Burn Wounds

Abstract

Peptide-based antimicrobial materials are recognized as promising alternatives to antibiotics to circumvent the emergence of antibiotic-resistant bacteria or to combat multiple resistant bacteria by targeting the bacterial cell membrane. The components and conformations of antimicrobial peptides are extensively explored to achieve broad-spectrum and effective antimicrobial activity. Here, star-shaped antimicrobial polypeptides are fabricated by employing homologs of poly(l-lysine)s (i.e., poly(l-ornithine)s, poly(l-lysine)s, and poly(l- ,-diaminoheptylic acid)s) with the aim of modulating their charge/hydrophobicity balance and rationalizing their structure-antimicrobial property relationships. The in vitro antibacterial investigation reveals that unnatural amino-acid-based star-shaped poly(l-ornithine)s have remarkable proteolytic stability, excellent biofilm-disrupting capacity, and broad-spectrum antimicrobial activity, even against difficult-to-kill Gram-negative Pseudomonas aeruginosa. Furthermore, star-shaped poly(l-ornithine)s significantly reduce the microbial burden and improve the burn wound healing of mouse skin infected with P. aeruginosa. These results demonstrate that unnatural amino-acid-based star-shaped poly(l-ornithine)s can serve as emerging long-term and biofilm-disrupting antimicrobial agents to treat biofilm-related infections in burn, especially caused by notorious P. aeruginosa.

Serum Amino Acid Levels and Mortality in Patients Undergoing Percutaneous Endoscopic Gastrostomy

“…24 Catabolic states such as burns affect the ornithine level in tissues in the body. 25 In the present study, it was found that the level of ornithine was increased in the follow-up of both the dead and surviving patients. The authors could not explain the relationship of ornithine level with both survival and mortality.…”

Membrane-disruptive peptides/peptidomimetics-based therapeutics: Promising systems to combat bacteria and cancer in the drug-resistant era

“…Furthermore, SMAMPs exhibit significant advantages over natural AMPs, such as enhanced antimicrobial activity, flexible framework for chemical modification, improved physicochemical stability, and better compatibility with drug-delivery methodology 53 . Recently, unnatural antibacterial peptidomimetics of various backbone structure have emerged with promising potential, such as poly( α -amino acid)s 54 , 55 , 56 , 57 , poly( β -amino acid)s 58 , 59 , polymethacrylate 60 , 61 , 62 , polymethacrylamide 63 , 64 , poly(2-oxazoline) 65 , 66 , polycarbonates 67 , 68 , polynorbornene 69 , 70 , peptidopolysaccharides 41 , 71 , poly(isobutylene- alt-N -alkyl maleimide) 72 , 73 , 74 , β -peptides 75 , peptoids, and AApeptides 76 , 77 , 78 , 79 , 80 . The antibacterial performance of these MDPs is primarily affected by factors, such as amphiphilicity, charge, cationic chemical functionality, molecular weight, sequence, biodegradability, and subunit stereoisomerism.…”

“…More recently, cationic star-shaped antimicrobials have been developed as unique molecular scaffolds that provide a high charge density for binding anionic bacterial bilayers 82 , 119 , 120 , 121 , 122 , 123 . Cai's group 55 , 56 , 57 highlighted that enhancing the cationic charge density of SMAMPs by transforming their backbone from linear to star-shaped could facilitate their electrostatic binding affinity toward bacterial cell membranes and give them a unique membrane perturbation capability ( Fig. 4 E).…”

“…, poly( l -ornithine)s (PLOs), PLLs, and poly( l - α , ζ -diaminoheptylic acid)) with varying numbers of methylene groups in their side chains. They found that unnatural amino acid-based star-shaped PLOs demonstrated enhanced charge density, broad-spectrum microbicidal activity, remarkable proteolytic stability, and an efficient biofilm-disruptive capacity against P. aeruginosa 56 . To overcome the poor membrane perturbation capability of these nonamphiphilic star-shaped polycations, they further introduced guanidinium into the system, finding that four-armed poly(arginine- alt -glycine) can interact with both the headgroups and unsaturated tails of phospholipids in bacterial membranes through multiple peptide‒membrane interactions, allowing it to penetrate deeper inside the biologically inaccessible high-energy barrier of the hydrophobic lipid bilayer interior to cause membrane permeabilization and intracellular-damaging action 57 .…”

De novo design of short antimicrobial lipopeptides

“…Some lipopeptides in solution could behave in a similar manner to antimicrobial peptides, since they can form micelles to reach high local concentrations with bactericidal effect (Chongsiriwatana et al 2011). The use of a few amino acids including Ornithine linked to the fatty acids provide stability, maintaining the antimicrobial activity at low concentrations (Meir et al 2017, Pan et al 2020.…”