Enhanced efficacy of synergistic combinations of antimicrobial peptides with caspofungin versus Candida albicans in insect and murine models of systemic infection
Enhanced efficacy of synergistic combinations of antimicrobial peptides with caspofungin versus Candida albicans in insect and murine models of systemic infection
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DOI：
10.1007/s10096-013-1850-8
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发表时间：
2013-08-01
影响因子：
4.5
通讯作者：
Coote, P. J.
中科院分区：
文献类型：
--
作者：
MacCallum, D. M.;Desbois, A. P.;Coote, P. J.
本研究的目的是确定抗菌肽 (AMP) 与卡泊芬净的组合是否在体外和体内表现出比白色念珠菌更强的抗真菌活性。选择了三种满足有利于其作为新型抗真菌剂潜在开发的标准的常规 AMP 进行研究。硫酸粘菌素也被列为临床使用的环肽抗生素。确定每种抗真菌药物的最低抑制浓度 (MIC)，并使用棋盘测定法确定 AMP 或粘菌素与卡泊芬净双重组合的分数抑制浓度指数 (FICI) 值。对相同的组合进行活力测定，以研究杀菌相互作用。然后测试协同抗真菌组合的体内功效，并在蜡蛾幼虫和全身白色念珠菌感染的小鼠模型中与单一疗法进行比较。与卡泊芬净联合使用时，每种 AMP [hMUC7-12、DsS3(1-16)、hLF(1-11)] 和粘菌素在体外均具有协同作用和念珠菌作用。与单一疗法相比，用卡泊芬净与 hMUC7-12、DsS3(1-16) 或粘菌素联合治疗受感染的蜡蛾幼虫可显着提高存活率。值得注意的是，与仅用单独药物治疗的组相比，用卡泊芬净和DsS3(1-16)的组合治疗白色念珠菌感染的小鼠可提高存活率。这项研究表明，含有卡泊芬净和 AMP 或粘菌素的联合疗法值得进一步开发，作为白色念珠菌感染的潜在新疗法。
The objective of this study was to determine whether combinations of antimicrobial peptides (AMPs) with caspofungin display enhanced antifungal activity versus Candida albicans in vitro and in vivo. Three conventional AMPs that satisfied criteria favouring their potential development as novel antifungals were selected for investigation. Colistin sulphate was also included as a cyclic peptide antibiotic used in the clinic. Minimum inhibitory concentrations (MICs) were determined for each antifungal agent and checkerboard assays were used to determine fractional inhibitory concentration index (FICI) values for dual combinations of AMPs or colistin with caspofungin. Viability assays were performed for the same combinations in order to investigate fungicidal interactions. Synergistic antifungal combinations were then tested for efficacy in vivo and compared to monotherapies in wax moth larva and murine models of systemic C. albicans infection. In combination with caspofungin, each of the AMPs [hMUC7-12, DsS3(1-16), hLF(1-11)] and colistin were synergistic and candidacidal in vitro. The treatment of infected wax moth larvae with combinations of caspofungin with hMUC7-12, DsS3(1-16) or colistin resulted in significant enhancements in survival compared to treatment with monotherapies. Notably, the treatment of C. albicans-infected mice with a combination of caspofungin and DsS3(1-16) resulted in the enhancement of survival compared to groups treated with just the individual agents. This study demonstrates that combination therapies containing caspofungin and AMPs or colistin merit further development as potential novel treatments for C. albicans infections.