PEGylation of Polyethylenimine Lowers Acute Toxicity while Retaining Anti-Biofilm and β-Lactam Potentiation Properties against Antibiotic-Resistant Pathogens.
PEGylation of Polyethylenimine Lowers Acute Toxicity while Retaining Anti-Biofilm and β-Lactam Potentiation Properties against Antibiotic-Resistant Pathogens.
复制标题
DOI：
10.1021/acsomega.0c04111
复制
发表时间：
2020-10-13
期刊：
影响因子：
4.1
通讯作者：
Rice CV
中科院分区：
文献类型：
--
作者：
Lam AK;Moen EL;Pusavat J;Wouters CL;Panlilio H;Ferrell MJ;Houck MB;Glatzhofer DT;Rice CV
细菌生物膜，通常是抗生素药物无法穿透的，是伤口愈合不良的主要原因。具有抗菌素耐药（AMR）细菌生物膜的伤口预后较差，如耐甲氧西林金黄色葡萄球菌（MRSA）、耐甲氧西林金黄表皮葡萄球菌（MRSE）和多药耐药铜绿假单胞菌（MDR-PA）。耐药性阻碍了标准抗生素的初始治疗。MRSA、MRSE和/或MDR-PA的持续存在通常使急性感染变成慢性伤口感染。低分子量（600 Da）支化聚乙烯亚胺（600 Da BPEI）的水溶性亲水性使药物输送变得容易，可以直接攻击伤口环境中的AMR和生物膜，作为伤口治疗的外用药物。为了减轻毒性问题，我们在简单的一步反应中用聚乙二醇（PEG）修饰了600 Da BPEI。PEG-BPEI分子使MRSA、MRSE和MDR-PA中的β-内酰胺抗性失效，同时还具有溶解已建立的生物膜的能力。PEG-BPEI独立地完成这些任务，产生多功能增效剂。我们设想用局部、口服或静脉内给予抗生素的伤口治疗，其中PEG-BPEI的外部应用使生物膜和抗性机制失效。在缺乏强大的新药管道的情况下，必须重新评估现有药物和方案与增效剂的组合。600 Da BPEI的聚乙二醇化提供了新的机会，以满足这一目标与单一的化合物，其多功能特性得到保留，同时降低急性毒性。
Bacterial biofilms, often impenetrable to antibiotic medications, are a leading cause of poor wound healing. The prognosis is worse for wounds with biofilms of antimicrobial-resistant (AMR) bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant S. epidermidis (MRSE), and multi-drug resistant Pseudomonas aeruginosa (MDR-PA). Resistance hinders initial treatment of standard-of-care antibiotics. The persistence of MRSA, MRSE, and/or MDR-PA often allows acute infections to become chronic wound infections. The water-soluble hydrophilic properties of low-molecular-weight (600 Da) branched polyethylenimine (600 Da BPEI) enable easy drug delivery to directly attack AMR and biofilms in the wound environment as a topical agent for wound treatment. To mitigate toxicity issues, we have modified 600 Da BPEI with polyethylene glycol (PEG) in a straightforward one-step reaction. The PEG–BPEI molecules disable β-lactam resistance in MRSA, MRSE, and MDR-PA while also having the ability to dissolve established biofilms. PEG-BPEI accomplishes these tasks independently, resulting in a multifunction potentiation agent. We envision wound treatment with antibiotics given topically, orally, or intravenously in which external application of PEG–BPEIs disables biofilms and resistance mechanisms. In the absence of a robust pipeline of new drugs, existing drugs and regimens must be re-evaluated as combination(s) with potentiators. The PEGylation of 600 Da BPEI provides new opportunities to meet this goal with a single compound whose multifunction properties are retained while lowering acute toxicity.
登录
查看更多内容
DOI：
10.1021/acs.langmuir.6b00240
发表时间：
2016-04-12
期刊：
Langmuir : the ACS journal of surfaces and colloids
影响因子：
--
作者：
Clifton LA;Ciesielski F;Skoda MW;Paracini N;Holt SA;Lakey JH
通讯作者：
Lakey JH
影响因子：
3.6
作者：
Gottlieb, HE;Kotlyar, V;Nudelman, A
通讯作者：
Nudelman, A
影响因子：
5.3
作者：
Konai, Mohini M.;Haldar, Jayanta
通讯作者：
Haldar, Jayanta
影响因子：
5.3
作者：
Burrows, Lori L.
通讯作者：
Burrows, Lori L.
影响因子：
6.2
作者：
Calabretta, Michelle K.;Kumar, Amit;Cai, Chengzhi
通讯作者：
Cai, Chengzhi