在小鼠体内的药代动力学和疗效研究中，分枝杆菌生物合成抑制剂水杨酰-AMS 的表现。
Pharmacokinetic and in vivo efficacy studies of the mycobactin biosynthesis inhibitor salicyl-AMS in mice.
机构信息
Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
出版信息
Antimicrob Agents Chemother. 2013 Oct;57(10):5138-40. doi: 10.1128/AAC.00918-13. Epub 2013 Jul 15.
Abstract
Mycobactin biosynthesis in Mycobacterium tuberculosis facilitates iron acquisition, which is required for growth and virulence. The mycobactin biosynthesis inhibitor salicyl-AMS [5'-O-(N-salicylsulfamoyl)adenosine] inhibits M. tuberculosis growth in vitro under iron-limited conditions. Here, we conducted a single-dose pharmacokinetic study and a monotherapy study of salicyl-AMS with mice. Intraperitoneal injection yielded much better pharmacokinetic parameter values than oral administration did. Monotherapy of salicyl-AMS at 5.6 or 16.7 mg/kg significantly inhibited M. tuberculosis growth in the mouse lung, providing the first in vivo proof of concept for this novel antibacterial strategy.
摘要
分枝杆菌(mycobacterium)中的分枝菌酸(mycobactin)生物合成有助于铁的获取，而铁是生长和毒力所必需的。分枝菌酸生物合成抑制剂水杨酰基-AMS[5'-O-(N-水杨酰基磺酰胺基)腺苷]可在铁限制条件下抑制结核分枝杆菌的体外生长。在这里，我们用小鼠进行了水杨酰基-AMS 的单次剂量药代动力学研究和单药治疗研究。腹腔注射比口服给药产生更好的药代动力学参数值。以 5.6 或 16.7mg/kg 的剂量单用水杨酰基-AMS 治疗可显著抑制小鼠肺部的结核分枝杆菌生长，为这一新的抗菌策略提供了首个体内概念验证。
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1
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PLoS Pathog. 2013 Jan;9(1):e1003120. doi: 10.1371/journal.ppat.1003120. Epub 2013 Jan 31.
2
Development of a selective activity-based probe for adenylating enzymes: profiling MbtA Involved in siderophore biosynthesis from Mycobacterium tuberculosis.用于腺苷酸化酶的基于活性的选择性探针的开发：对参与结核分枝杆菌铁载体生物合成的MbtA进行分析。
ACS Chem Biol. 2012 Oct 19;7(10):1653-8. doi: 10.1021/cb300112x. Epub 2012 Jul 23.
3
Mutational and phylogenetic analyses of the mycobacterial mbt gene cluster.分枝杆菌 mbt 基因簇的突变和系统发育分析。
J Bacteriol. 2011 Nov;193(21):5905-13. doi: 10.1128/JB.05811-11. Epub 2011 Aug 26.
4
PA-824 exhibits time-dependent activity in a murine model of tuberculosis.PA-824 在结核分枝杆菌感染的小鼠模型中表现出时间依赖性活性。
Antimicrob Agents Chemother. 2011 Jan;55(1):239-45. doi: 10.1128/AAC.00849-10. Epub 2010 Oct 11.
5
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6
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Nat Chem Biol. 2005 Jun;1(1):29-32. doi: 10.1038/nchembio706. Epub 2005 May 24.
7
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J Med Chem. 2006 Jan 12;49(1):31-4. doi: 10.1021/jm051060o.
8
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9
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