Clinical and Health Science, University of South Australia, North Tce, Adelaide, South Australia 5000, Australia.
The Basil Hetzel Institute for Translational Health Research, Woodville, South Australia 5011, Australia.
ACS Infect Dis. 2021 Aug 13;7(8):2102-2115. doi: 10.1021/acsinfecdis.1c00014. Epub 2021 Apr 28.
The glycoside hydrolase, PslG, attacks and degrades the dominant Psl polysaccharide in the exopolymeric substance (EPS) matrix of biofilms and is a promising therapy to potentiate the effect of antibiotics. However, the need for coadministration with an antibiotic and the potential susceptibility of PslG to proteolysis highlights the need for an effective delivery system. Here, we compared liposomes versus lipid liquid crystal nanoparticles (LCNPs) loaded with PslG and tobramycin as potential formulation approaches to (1) protect PslG from proteolysis, (2) trigger the enzyme's release in the presence of bacteria, and (3) improve the total antimicrobial effect and in a infection model. LCNPs were an effective formulation strategy for PslG and tobramycin that better protected the enzyme against proteolysis, triggered and sustained the release of PslG, improved the antimicrobial effect by 10-100-fold, and increased the survival of infected with Digestible LCNPs had the advantage of triggering the enzyme's release in the presence of bacteria. However, compared to nondigestible LCNPs, negligible differences arose between the LCNPs' ability to protect PslG from proteolysis and potentiate the antimicrobial activity in combination with tobramycin. In the improved antimicrobial efficacy was comparable to tobramycin-LCNPs, although the PslG + tobramycin-LCNPs achieved a greater than 10-fold reduction in bacteria compared to the unformulated combination. Herewith, LCNPs are showcased as a promising protective delivery system for novel biofilm dispersing enzymes combined with antibiotics, enabling infection-directed therapy and improved performance.
糖苷水解酶 PslG 可攻击并降解生物膜中胞外聚合物 (EPS) 基质中占主导地位的 Psl 多糖，是一种增强抗生素作用的有前途的治疗方法。然而，需要与抗生素联合使用，并且 PslG 可能容易被蛋白水解，这突出了需要有效的递送系统。在这里，我们比较了载有 PslG 和妥布霉素的脂质体与脂质液晶纳米颗粒 (LCNP)，作为潜在的制剂方法，以实现以下目标：(1) 保护 PslG 免受蛋白水解，(2) 在存在细菌的情况下触发酶的释放，以及 (3) 提高总抗菌效果和在感染模型中。LCNP 是 PslG 和妥布霉素的有效制剂策略，可更好地保护酶免受蛋白水解，触发并持续释放 PslG，将抗菌效果提高 10-100 倍，并提高感染的存活率。可消化的 LCNP 具有在存在细菌时触发酶释放的优势。然而，与不可消化的 LCNP 相比，LCNP 保护 PslG 免受蛋白水解和与妥布霉素联合增强抗菌活性的能力之间几乎没有差异。在感染模型中，改良的抗菌功效与妥布霉素-LCNP 相当，尽管 PslG + 妥布霉素-LCNP 与未配制的组合相比，细菌减少了 10 倍以上。由此可见，LCNP 作为一种有前途的新型生物膜分散酶与抗生素的保护性递送系统，可实现靶向感染的治疗和性能提升。
