Sofokleous Panagiotis, Ali Shanom, Wilson Peter, Buanz Asma, Gaisford Simon, Mistry Dharmit, Fellows Adrian, Day Richard M
Division of Medicine, University College London, Gower Street, London WC1E 6BT, UK.
Environmental Research Laboratory, University College Hospital, 235 Euston Road, London NW1 2BU, UK.
Acta Biomater. 2017 Dec;64:301-312. doi: 10.1016/j.actbio.2017.10.001. Epub 2017 Oct 3.
The spread of antibiotic-resistant pathogens requires new treatments. Small molecule precursor compounds that produce oxidative biocides with well-established antimicrobial properties could provide a range of new therapeutic products to combat resistant infections. The aim of this study was to investigate a novel biomaterials-based approach for the manufacture, targeted delivery and controlled release of a peroxygen donor (sodium percarbonate) combined with an acetyl donor (tetraacetylethylenediamine) to deliver local antimicrobial activity via a dynamic equilibrium mixture of hydrogen peroxide and peracetic acid. Entrapment of the pre-cursor compounds into hierarchically structured degradable microparticles was achieved using an innovative dry manufacturing process involving thermally induced phase separation (TIPS) that circumvented compound decomposition associated with conventional microparticle manufacture. The microparticles provided controlled release of hydrogen peroxide and peracetic acid that led to rapid and sustained killing of multiple drug-resistant organisms (methicillin-resistant Staphylococcus aureus and carbapenem-resistant Escherichia coli) without associated cytotoxicity in vitro nor intracutaneous reactivity in vivo. The results from this study demonstrate for the first time that microparticles loaded with acetyl and peroxygen donors retain their antimicrobial activity whilst eliciting no host toxicity. In doing so, it overcomes the detrimental effects that have prevented oxidative biocides from being used as alternatives to conventional antibiotics.
The manuscript explores a novel approach to utilize the antimicrobial activity of oxidative species for sustained killing of multiple drug-resistant organisms without causing collateral tissue damage. The results demonstrate, for the first time, the ability to load pre-cursor compounds into porous polymeric structures that results in their release and conversion into oxidative species in a controlled manner. Until now, the use of oxidative species has not been considered as a candidate therapeutic replacement for conventional antibiotics due to difficulties associated with handling during manufacture and controlling sustained release without causing undesirable tissue damage. The ultimate impact of the research could be the creation of new materials-based anti-infective chemotherapeutic agents that have minimal potential for giving rise to antimicrobial resistance.
抗生素耐药病原体的传播需要新的治疗方法。能够产生具有公认抗菌特性的氧化性杀菌剂的小分子前体化合物可为对抗耐药感染提供一系列新的治疗产品。本研究的目的是探究一种基于生物材料的新方法，用于制备、靶向递送和控释过氧供体（过碳酸钠）与乙酰供体（四乙酰乙二胺）的组合，通过过氧化氢和过氧乙酸的动态平衡混合物来提供局部抗菌活性。使用一种创新的干法制造工艺，即热致相分离（TIPS），将前体化合物包封到具有层次结构的可降解微粒中，该工艺避免了与传统微粒制造相关的化合物分解。这些微粒实现了过氧化氢和过氧乙酸的控释，导致对多种耐药菌（耐甲氧西林金黄色葡萄球菌和耐碳青霉烯大肠杆菌）的快速且持续杀灭，在体外无相关细胞毒性，在体内无皮内反应性。本研究结果首次证明，负载乙酰和过氧供体的微粒在不引起宿主毒性的情况下保留其抗菌活性。这样做，它克服了阻碍氧化性杀菌剂用作传统抗生素替代品的有害影响。
该手稿探索了一种利用氧化物质的抗菌活性来持续杀灭多种耐药菌而不造成附带组织损伤的新方法。结果首次证明了将前体化合物负载到多孔聚合物结构中的能力，这导致它们以可控方式释放并转化为氧化物质。到目前为止，由于在制造过程中处理困难以及难以控制持续释放而不引起不良组织损伤，氧化物质尚未被视为传统抗生素的候选治疗替代品。该研究的最终影响可能是创造出基于新材料的抗感染化疗药物，其产生抗菌耐药性的可能性极小。
