Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
Department of Medical Microbiology and Infection Control, VU University Medical Center, Amsterdam, The Netherlands.
Clin Transl Sci. 2020 Nov;13(6):1060-1064. doi: 10.1111/cts.12793. Epub 2020 May 10.
The zebrafish infected with Mycobacterium marinum (M. marinum) is an attractive tuberculosis disease model, showing similar pathogenesis to Mycobacterium tuberculosis (M. tuberculosis) infections in humans. To translate pharmacological findings from this disease model to higher vertebrates, a quantitative understanding of the natural growth of M. marinum in comparison to the natural growth of M. tuberculosis is essential. Here, the natural growth of two strains of M. marinum, E11 and M , is studied over an extended period using an established model-based approach, the multistate tuberculosis pharmacometric (MTP) model, for comparison to that of M. tuberculosis. Poikilotherm-derived strain E11 and human-derived strain M were grown undisturbed up to 221 days and viability of cultures (colony forming unit (CFU)/mL) was determined by plating at different time points. Nonlinear mixed effects modeling using the MTP model quantified the bacterial growth, the transfer among fast, slow, and non-multiplying states, and the inoculi. Both strains showed initial logistic growth, reaching a maximum after 20-25 days for E11 and M , respectively, followed by a decrease to a new plateau. Natural growth of both E11 and M was best described with Gompertz growth functions. For E11, the inoculum was best described in the slow-multiplying state, for M in the fast-multiplying state. Natural growth of E11 was most similar to that of M. tuberculosis, whereas M showed more aggressive growth behavior. Characterization of natural growth of M. marinum and quantitative comparison with M. tuberculosis brings the zebrafish tuberculosis disease model closer to the quantitative translational pipeline of antituberculosis drug development.
感染海分枝杆菌（Mycobacterium marinum，M. marinum）的斑马鱼是一种有吸引力的结核病疾病模型，其发病机制与人类分枝杆菌（Mycobacterium tuberculosis，M. tuberculosis）感染相似。为了将该疾病模型中的药理学发现转化为高等脊椎动物，定量了解海分枝杆菌与结核分枝杆菌的自然生长情况至关重要。在这里，使用已建立的基于模型的方法——多状态结核药代动力学（multistate tuberculosis pharmacometric，MTP）模型，对两种海分枝杆菌菌株 E11 和 M 的自然生长进行了长达 221 天的扩展研究，并与结核分枝杆菌进行了比较。来源于变温动物的菌株 E11 和来源于人类的菌株 M 未经干扰地生长，直至 221 天，并通过不同时间点的平板培养来确定培养物的存活率（菌落形成单位（colony forming unit，CFU）/mL）。使用 MTP 模型进行非线性混合效应建模，定量了细菌的生长、快速、缓慢和非倍增状态之间的转移以及接种物。两种菌株均表现出初始逻辑增长，E11 和 M 分别在 20-25 天后达到最大值，随后下降到新的平台。E11 和 M 的自然生长均最好用 Gompertz 生长函数来描述。对于 E11，接种物最好在缓慢倍增状态下描述，对于 M，最好在快速倍增状态下描述。E11 的自然生长与结核分枝杆菌最相似，而 M 则表现出更为激进的生长行为。海分枝杆菌自然生长的特征描述以及与结核分枝杆菌的定量比较，使斑马鱼结核病疾病模型更接近抗结核药物开发的定量转化管道。
