A Conformationally Constrained Cyclic Acyldepsipeptide Is Highly Effective in Mice Infected with Methicillin-Susceptible and -Resistant Staphylococcus aureus.
A Conformationally Constrained Cyclic Acyldepsipeptide Is Highly Effective in Mice Infected with Methicillin-Susceptible and -Resistant Staphylococcus aureus.
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DOI：
10.1371/journal.pone.0153912
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Mylonakis E
中科院分区：
文献类型：
--
作者：
Arvanitis M;Li G;Li DD;Cotnoir D;Ganley-Leal L;Carney DW;Sello JK;Mylonakis E
环酰基降肽（ADEP）是一类新型抗菌剂，其中一些（如ADEP 4）对革兰氏阳性细菌具有高度活性。这些体内研究的重点是ADEP B315，这是一种设计合理的化合物，具有迄今为止报道的任何ADEP类似物中最有效的体外活性。采用甲氧西林敏感金黄色葡萄球菌（MSSA）和甲氧西林耐药菌株（MRSA）腹腔致死性小鼠感染模型进行体内药效实验。感染小鼠用ADEP B315、ADEP 4的去甲基类似物、万古霉素或用于ADEP的载药治疗，每天评估它们的生存情况。接种msa感染小鼠后立即处死，测定其肝脏和脾脏的细菌负荷。采用人全血培养法测定ADEP B315的毒性。在MSSA实验中，所有小鼠在24小时内感染死亡。所有被试化合物均能有效延长感染小鼠的生存期（p<0.001）。用ADEP B315处理的小鼠10天存活率为39%，而去甲基ADEP 4类似物处理的小鼠10天存活率为7% （p = 0.017）。用ADEP B315治疗感染小鼠的存活率与用vanocmycin治疗相同剂量的小鼠相当（p = 0.12）。此外，与对照组相比，经ADEP B315处理的小鼠肝脏和脾脏的细菌负荷显著降低。在MRSA实验中，与用载药（p = 0.001）或万古霉素（p = 0.007）处理的小鼠相比，ADEP B315能够显著延长存活时间。当ADEP B315浓度达到25 μg/ml时，对人全血培养物无明显毒性。ADEP B315是安全的，可以治愈患有甲氧西林敏感和耐药金黄色葡萄球菌菌株致命感染的小鼠。
Cyclic acyldepsipeptides (ADEPs) are a novel class of antibacterial agents, some of which (e.g., ADEP 4) are highly active against Gram-positive bacteria. The focus of these in vivo studies is ADEP B315, a rationally designed compound that has the most potent in vitro activity of any ADEP analog reported to date. In vivo efficacy experiments were performed using lethal intraperitoneal mice infection models with a methicillin-sensitive S. aureus (MSSA) and a methicillin-resistant (MRSA) strain. The infected mice were treated with ADEP B315, a des-methyl analog of ADEP 4, vancomycin, or the vehicle used for the ADEPs and their survival was assessed daily. A subset of MSSA-infected mice was sacrificed soon after inoculation and the bacterial burden was measured in their livers and spleens. The toxicity of ADEP B315 was assessed in viability assays using human whole blood cultures. In the MSSA experiments, all mice treated with the vehicle succumbed to the infection within 24 hours. All tested compounds were effective in prolonging survival of infected mice (p<0.001). Mice treated with ADEP B315 had a 39% survival rate by 10 days compared to 7% survival in mice treated with a des-methyl ADEP 4 analog (p = 0.017). Survival of the infected mice treated with ADEP B315 was comparable to those treated with vanocmycin (p = 0.12) at the same dose. Further, bacterial burden in the liver and spleen was significantly lower in mice treated with ADEP B315 compared to controls. In the MRSA experiments, ADEP B315 was able to significantly prolong survival compared to mice treated with either the vehicle (p = 0.001) or vancomycin (p = 0.007). ADEP B315 exhibited no significant toxicity in human whole blood cultures at concentrations up to 25 μg/ml. ADEP B315 is safe and can cure mice that have lethal infections of methicillin-sensitive and -resistant strains of S. aureus.