Designed Host Defense Peptides for the Treatment of Bacterial Keratitis.
Designed Host Defense Peptides for the Treatment of Bacterial Keratitis.
复制标题
DOI：
10.1167/iovs.17-22243
复制
发表时间：
2017-12-01
影响因子：
4.4
通讯作者：
Woodburn KW
中科院分区：
文献类型：
--
作者：
Clemens LE;Jaynes J;Lim E;Kolar SS;Reins RY;Baidouri H;Hanlon S;McDermott AM;Woodburn KW
为了限制角膜损伤和潜在的视力丧失，细菌性角膜炎必须积极治疗。由于需要经验性治疗和细菌耐药性的迅速出现，需要抗菌药物的创新。设计的宿主防御肽（dHDP）是天然存在的HDP的合成类似物，其提供对入侵病原体的防御。本研究调查了新型dHDP用于治疗细菌性角膜炎的用途。测定dHDP对革兰氏阳性菌和革兰氏阴性菌的最小抑菌浓度（MIC）。测定最小生物膜根除浓度（MBEC）和体外时间杀灭试验。在鼠铜绿假单胞菌角膜炎模型中评价最具活性的dHDP RP 444诱导耐药性的倾向和治疗益处。设计的HDPs具有杀菌性，MIC范围为2至> 64 μ g/mL，MBEC范围为6至750 μ g/mL。在时间杀灭试验中，dHDPs能够在接触低至2 μ g/mL时迅速减少细菌计数。在铜绿假单胞菌重复暴露于亚抑制浓度后，RP 444未诱导耐药性。RP 444在细菌性角膜炎的鼠模型中表现出显著的功效，如通过眼部临床评分的显著剂量依赖性降低、显著降低的细菌负荷和显著降低的炎性细胞浸润所证明的。创新的dHDPs显示出有效的抗微生物活性，具有有限的耐药性发展潜力，并降低了小鼠铜绿假单胞菌角膜炎的严重程度。这些研究表明，一种新的dHDP可能有潜力治疗威胁视力的细菌性角膜炎患者。
To limit corneal damage and potential loss of vision, bacterial keratitis must be treated aggressively. Innovation in antimicrobials is required due to the need for empirical treatment and the rapid emergence of bacterial resistance. Designed host defense peptides (dHDPs) are synthetic analogues of naturally occurring HDPs, which provide defense against invading pathogens. This study investigates the use of novel dHDPs for the treatment of bacterial keratitis. The minimum inhibitory concentrations (MICs) were determined for dHDPs on both Gram-positive and -negative bacteria. The minimum biofilm eradication concentrations (MBEC) and in vitro time-kill assays were determined. The most active dHDP, RP444, was evaluated for propensity to induce drug resistance and therapeutic benefit in a murine Pseudomonas aeruginosa keratitis model. Designed HDPs were bactericidal with MICs ranging from 2 to >64 μg/mL and MBEC ranging from 6 to 750 μg/mL. In time-kill assays, dHDPs were able to rapidly reduce bacterial counts upon contact with as little as 2 μg/mL. RP444 did not induce resistance after repeated exposure of P. aeruginosa to subinhibitory concentrations. RP444 demonstrated significant efficacy in a murine model of bacterial keratitis as evidenced by a significant dose-dependent decrease in ocular clinical scores, a significantly reduced bacterial load, and substantially decreased inflammatory cell infiltrates. Innovative dHDPs demonstrated potent antimicrobial activity, possess a limited potential for development of resistance, and reduced the severity of murine P. aeruginosa keratitis. These studies demonstrate that a novel dHDP may have potential to treat patients with sight-threatening bacterial keratitis.
登录
查看更多内容
影响因子：
4.6
作者：
Gee, Michelle L.;Burton, Matthew;Grevis-James, Alistair;Hossain, Mohammed Akhter;McArthur, Sally;Palombo, Enzo A.;Wade, John D.;Clayton, Andrew H. A.
通讯作者：
Clayton, Andrew H. A.
影响因子：
6.4
作者：
Hamblin, MR;Zahra, T;Hasan, T
通讯作者：
Hasan, T
影响因子：
2
作者：
Cole, N;Hume, E;Willcox, MDP
通讯作者：
Willcox, MDP
影响因子：
3
作者：
Mangoni, Maria Luisa;Luca, Vincenzo;McDermott, Alison M.
通讯作者：
McDermott, Alison M.
FDU-12介孔道对MoS2活性相的孔限域效应及其加氢脱硫性能
影响因子：
--
作者：
Liu, Cong;Yuan, Pei;Cui, Chunsheng
通讯作者：
Cui, Chunsheng