Harnessing ultrasound-stimulated phase change contrast agents to improve antibiotic efficacy against methicillin-resistant Staphylococcus aureus biofilms.
Harnessing ultrasound-stimulated phase change contrast agents to improve antibiotic efficacy against methicillin-resistant Staphylococcus aureus biofilms.
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利用超声刺激的相位变化对比剂，以提高针对耐甲氧西林的金黄色葡萄球菌生物膜的抗生素疗效。
DOI：
10.1016/j.bioflm.2021.100049
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发表时间：
2021-12
期刊：
影响因子：
6.8
通讯作者：
Rowe SE
中科院分区：
文献类型：
--
作者：
Durham PG;Sidders AE;Beam JE;Kedziora KM;Dayton PA;Conlon BP;Papadopoulou V;Rowe SE
细菌生物膜通常与慢性感染相关，对抗生素治疗反应不佳，经常需要手术干预。生物膜中含有持久细胞，代谢惰性细胞，对大多数常规抗生素具有耐受性。此外，生物膜基质可以作为物理屏障，阻碍抗生素的扩散。新的治疗方法经常提高生物膜杀伤，但通常无法实现根除。未能根除生物膜导致慢性和复发性感染，与主要的财务医疗保健成本和显著的发病率和死亡率相关。我们通过双管齐下的策略解决了这个问题，使用1）靶向持久细胞的抗生素和2）超声刺激相变造影剂（US-PCCA），这可以提高抗生素的渗透性。我们以前证明，铜绿假单胞菌产生的鼠李糖脂，可以诱导革兰氏阳性菌的氨基糖苷类摄取，导致持续性细胞死亡。我们还表明，US-PCCA可以瞬时破坏生物屏障，以改善治疗性大分子的渗透。我们假设，联合使用靶向持留细胞的抗生素和US-PCCA以提高药物渗透性，可以改善对甲氧西林耐药的S。金黄色葡萄球菌（MRSA）生物膜。单独使用氨基糖苷类或与US-PCCA联合使用对MRSA生物膜的疗效有限。相比之下，鼠李糖脂和氨基糖苷类的抗持久性组合与US-PCCA组合显著提高了生物膜杀灭。这种新型治疗策略具有快速临床转化的潜力，因为PCCA制剂是FDA批准的超声造影剂的变体，已经在临床实践中使用，并且我们研究中使用的低压超声设置可以在低于FDA设定的诊断成像限值的压力下使用现有超声硬件实现。
Bacterial biofilms, often associated with chronic infections, respond poorly to antibiotic therapy and frequently require surgical intervention. Biofilms harbor persister cells, metabolically indolent cells, which are tolerant to most conventional antibiotics. In addition, the biofilm matrix can act as a physical barrier, impeding diffusion of antibiotics. Novel therapeutic approaches frequently improve biofilm killing, but usually fail to achieve eradication. Failure to eradicate the biofilm leads to chronic and relapsing infection, is associated with major financial healthcare costs and significant morbidity and mortality. We address this problem with a two-pronged strategy using 1) antibiotics that target persister cells and 2) ultrasound-stimulated phase-change contrast agents (US-PCCA), which improve antibiotic penetration. We previously demonstrated that rhamnolipids, produced by Pseudomonas aeruginosa, could induce aminoglycoside uptake in gram-positive organisms, leading to persister cell death. We have also shown that US-PCCA can transiently disrupt biological barriers to improve penetration of therapeutic macromolecules. We hypothesized that combining antibiotics which target persister cells with US-PCCA to improve drug penetration could improve treatment of methicillin resistant S. aureus (MRSA) biofilms. Aminoglycosides alone or in combination with US-PCCA displayed limited efficacy against MRSA biofilms. In contrast, the anti-persister combination of rhamnolipids and aminoglycosides combined with US-PCCA dramatically improved biofilm killing. This novel treatment strategy has the potential for rapid clinical translation as the PCCA formulation is a variant of FDA-approved ultrasound contrast agents that are already in clinical practice and the low-pressure ultrasound settings used in our study can be achieved with existing ultrasound hardware at pressures below the FDA set limits for diagnostic imaging.
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影响因子：
2.9
作者：
Fix, Samantha M.;Koppolu, Bhanu P.;Papadopoulou, Virginie
通讯作者：
Papadopoulou, Virginie
影响因子：
2.9
作者：
Helfield, Brandon L.;Yoo, Kimoon;Burns, Peter N.
通讯作者：
Burns, Peter N.
影响因子：
4.9
作者：
Chiang, Wen-Chi;Nilsson, Martin;Tolker-Nielsen, Tim
通讯作者：
Tolker-Nielsen, Tim
影响因子：
2.9
作者：
Burgess MT;Porter TM
通讯作者：
Porter TM
DOI：
10.1073/pnas.1914906117
发表时间：
2020-06-09
影响因子：
11.1
作者：
Ilovitsh, Tali;Feng, Yi;Ferrara, Katherine W.
通讯作者：
Ferrara, Katherine W.