Controlled Block Polypeptide Composed of d-Type Amino Acids: A Therapeutics Delivery Platform to Inhibit Biofilm Formation of Drug-Resistant Bacteria

Abstract

Antibiotic resistance of bacteria has been widely developed due to biofilm protection and separating the bacteria from antibiotics. The phenomenon of biofilm inhibition or disassembly by D-amino acids (DAAs) has been reported recently, while it was also challenged by some other scientists. Presuming DAAs work for biofilms on the surface of bacteria, delivery of the DAAs to disease sites is important while small DAAs are easily removed by kidney. To resolve the above issues, it is urgent to develop a biofilm inhibitor. To achieve this goal, we synthesized D-type polypeptides via NCA ring-opening polymerization with the initiator of HMDS to generate poly(CBZ-L-lysine) 33 -block-poly(D-phenylalanine) 14 . After deprotection, the resultant polypeptides were converted into amphiphilic poly(L-lysine) 33 -blockpoly(D-phenylalanine) 14 , which can be self-assembled into well-defined homogeneous nanoparticles capable of capsulizing penicillin G. For the molecular weight of polypeptides resulting in various bioeffects, we prepared similar-sized polypeptides of an L-type equivalent polypeptide as control. The data from microbial experiments indicated that poly(L-lysine) 33 -block-poly(D-phenylalanine) 14 can inhibit biofilm formation of Bacillus subtilis at a low final concentration (24 μg/mL), much stronger than poly(L-lysine) 40 -block-poly(L-phenylalanine) 19 at the same concentration. This is the first report in that synthetic D-type polypeptides can inhibit biofilms of bacteria. Poly(L-lysine) 33 -block-poly(D-phenylalanine) 14 can be assembled into well-defined, biostable homogeneous nanoparticles. This research provides a potential solution to overcome bacteria antibiotic resistance from small molecules to material sciences and gives a unique angle to understand the current dispute if DAAs can disassemble the biofilms. Additionally, these nanoparticles have great potential in the development of nanomedicines with a longer circulation time in blood and this discovery has implications in developing antimicrobial nanodevices for therapy and basic scientific interest.

Inhibition and eradication of bacterial biofilm using polymeric materials

“…Chen and co-workers 92 demonstrated the biofilm disassembly and inhibition ability of cationic D-type polypeptides, as D-type amino acids (DAAs) were found to prevent existing biofilm, 93,94 though it is questioned by many scientists. The amphiphilic polypeptide, poly(L-lysine) 33 -block-poly(D-phenylalanine) 14 was synthesized by N-carboxyanhydride (NCA) ringopening polymerization using hexamethyldisilazane (HMDS) as an initiator.…”

Recent Nanotechnologies to Overcome the Bacterial Biofilm Matrix Barriers

“…synthesized a poly(CBZ‐l‐lysine) 33 ‐block‐poly(d‐phenylalanine) 14 d‐type polypeptide via an N ‐carboxyanhydride ring‐opening polymerization reaction, which can self‐assemble into nanocapsules for penicillin G delivery. [ 129 ] Gingerol is the main component of ginger, which reduces biofilm formation by interfering with the interaction between an extracellular diffusible N ‐(3‐oxododecanoyl)‐ l ‐homoserine lactone (OdDHL) and its cognate receptor LasR in P. aeruginosa . [ 124 ] In Byun's further study, the impacts of the different parts of (S)‐6‐gingerol were demonstrated (Figure 8D).…”

We Are One: Multispecies Metabolism of a Biofilm Consortium and Their Treatment Strategies

“…Using Dispersin B, a biofilm-dispersing enzyme, in combination with peptides, eradicated ∼70% of S. epidermidis biofilms compared to only ∼35% by Dispersin B alone ( Chen and Lee, 2018 ). Further, D-amino acids from B. subtilis , known to signal for biofilm disassembly, were found to inhibit the development of S. aureus biofilms ( Chen et al, 2020 ). Intriguingly, honey – a natural product, has also shown anti-biofilm effects by inhibiting P. aeruginosa biofilm formation and reducing its established biofilms ( Lu et al, 2019 ).…”