Combination of Mycobacterium tuberculosis RS Ratio and CFU Improves the Ability of Murine Efficacy Experiments to Distinguish between Drug Treatments.
Combination of Mycobacterium tuberculosis RS Ratio and CFU Improves the Ability of Murine Efficacy Experiments to Distinguish between Drug Treatments.
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DOI：
10.1128/aac.02310-21
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发表时间：
2022-04-19
影响因子：
4.9
通讯作者：
Walter, Nicholas D.
中科院分区：
文献类型：
--
作者：
Dide-Agossou, Christian;Bauman, Allison A.;Ramey, Michelle E.;Rossmassler, Karen;Al Mubarak, Reem;Pauly, Samantha;Voskuil, Martin, I;Garcia-Cremades, Maria;Savic, Rada M.;Nahid, Payam;Moore, Camille M.;Tasneen, Rokeya;Nuermberger, Eric L.;Robertson, Gregory T.;Walter, Nicholas D.
关键词：
小鼠结核病药物疗效研究历来以肺组织匀浆中结核分枝杆菌的CFU为基础监测细菌负荷。在另一种方法中，最近描述的一种称为RS比率的分子药效学标记量化了药物对基本细胞过程-正在进行的rRNA合成-的影响。在这里，我们在两个机构的三个BALB/c小鼠实验中评估了不同的药效学标志物区分治疗的能力。我们证实，不同的药效学标志物衡量不同的生物学反应。我们发现，药效学标志物的组合比任何单一标志物都能更好地区分治疗。RS比率与CFU的结合显示出最能概括方案治疗的等级顺序-缩短活性的能力，为同时评估衡量不同性质的药效学标志物将增强从动物模型中获得的洞察力和加速新联合方案的开发提供了概念证明。这些结果表明，有可能进入一个新的时代，在这个时代，抗菌治疗的评估不仅要基于细菌负担的培养测量，而且还要基于表明药物如何影响病原体生理状态的分子分析。
Murine tuberculosis drug efficacy studies have historically monitored bacterial burden based on CFU of Mycobacterium tuberculosis in lung homogenate. In an alternative approach, a recently described molecular pharmacodynamic marker called the RS ratio quantifies drug effect on a fundamental cellular process, ongoing rRNA synthesis. Here, we evaluated the ability of different pharmacodynamic markers to distinguish between treatments in three BALB/c mouse experiments at two institutions. We confirmed that different pharmacodynamic markers measure distinct biological responses. We found that a combination of pharmacodynamic markers distinguishes between treatments better than any single marker. The combination of the RS ratio with CFU showed the greatest ability to recapitulate the rank order of regimen treatment-shortening activity, providing proof of concept that simultaneous assessment of pharmacodynamic markers measuring different properties will enhance insight gained from animal models and accelerate development of new combination regimens. These results suggest potential for a new era in which antimicrobial therapies are evaluated not only on culture-based measures of bacterial burden but also on molecular assays that indicate how drugs impact the physiological state of the pathogen.
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影响因子：
5.2
作者：
Hu Y;Liu A;Ortega-Muro F;Alameda-Martin L;Mitchison D;Coates A
通讯作者：
Coates A
影响因子：
4.9
作者：
Lenaerts, AJ;Gruppo, V;Orme, IM
通讯作者：
Orme, IM
DOI：
10.1164/rccm.201604-0769oc
发表时间：
2016-12-15
影响因子：
24.7
作者：
Chengalroyen, Melissa D.;Beukes, Germar M.;Kana, Bavesh D.
通讯作者：
Kana, Bavesh D.
影响因子：
4.9
作者：
Kelly, BP;Furney, SK;Orme, IM
通讯作者：
Orme, IM
影响因子：
3.2
作者：
de Knegt, Gerjo J.;Dickinson, Laura;de Steenwinkel, Jurriaan E. M.
通讯作者：
de Steenwinkel, Jurriaan E. M.