Development of a novel aortic dissection mouse model and evaluation of drug efficacy using in-vivo assays and database analyses

ABSTRACT Effective tuberculosis treatment requires at least 6 months of combination therapy. Alterations in the physiological state of the bacterium during infection are thought to reduce drug efficacy and prolong the necessary treatment period, but the nature of these adaptations remain incompletely defined. To identify specific bacterial functions that limit drug effects during infection, we employed a comprehensive genetic screening approach to identify mutants with altered susceptibility to the first-line antibiotics in the mouse model. We identified many mutations that increase the rate of bacterial clearance, suggesting new strategies for accelerating therapy. In addition, the drug-specific effects of these mutations suggested that different antibiotics are limited by distinct factors. Rifampin efficacy is inferred to be limited by cellular permeability, whereas isoniazid is preferentially affected by replication rate. Many mutations that altered bacterial clearance in the mouse model did not have an obvious effect on drug susceptibility using in vitro assays, indicating that these chemical-genetic interactions tend to be specific to the in vivo environment. This observation suggested that a wide variety of natural genetic variants could influence drug efficacy in vivo without altering behavior in standard drug-susceptibility tests. Indeed, mutations in a number of the genes identified in our study are enriched in drug-resistant clinical isolates, identifying genetic variants that may influence treatment outcome. Together, these observations suggest new avenues for improving therapy, as well as the mechanisms of genetic adaptations that limit it. IMPORTANCE Understanding how Mycobacterium tuberculosis survives during antibiotic treatment is necessary to rationally devise more effective tuberculosis (TB) chemotherapy regimens. Using genome-wide mutant fitness profiling and the mouse model of TB, we identified genes that alter antibiotic efficacy specifically in the infection environment and associated several of these genes with natural genetic variants found in drug-resistant clinical isolates. These data suggest strategies for synergistic therapies that accelerate bacterial clearance, and they identify mechanisms of adaptation to drug exposure that could influence treatment outcome.

Download Full-text

In Vivo Detection and Measurement of Aortic Aneurysm and Dissection in Mouse Models Using Microcomputed Tomography with Contrast Agent

Contrast Media & Molecular Imaging ◽

10.1155/2019/5940301 ◽

2019 ◽

Vol 2019 ◽

pp. 1-9

Author(s):

Guanglang Zhu ◽

Huiying Sun ◽

Jiannan Wang ◽

Zhiqing Zhao ◽

Junmin Bao ◽

...

Keyword(s):

Aortic Aneurysm ◽

Aortic Dissection ◽

Mouse Model ◽

Contrast Agent ◽

Time Dependent ◽

Micro Ct ◽

Aortic Aneurysm And Dissection ◽

Dependent Signal ◽

Changing Process

Objectives. The aim of this study was to evaluate the potential of microcomputed tomography (micro-CT) using the intravascular contrast agent ExiTron nano 12000 for aorta imaging and monitoring the dynamic changing process of the aorta in mouse models with aortic aneurysm and dissection. Materials and Methods. Experiments were performed on healthy mice and mice with aortic dissection. Mice that were developing aortic dissection and healthy mice underwent micro-CT imaging after injection of ExiTron nano 12000. Time-dependent signal enhancement (at 1, 2, 3, 6, and 12 hours after intravenous injection of the contrast agent, respectively) in the aorta of healthy mice was measured to confirm the optimal imaging time of aorta. Various contrast agent doses (70, 100, and 150 μl per 25 g mouse, respectively) were investigated to determine the optimal required dose for imaging of the aorta. The mice were scanned with micro-CT at 1, 14, and 28 days after onset of aneurysm and dissection to monitor the dynamic changing process of the aorta. Mouse aortas were stained with hematoxylin and eosin staining, and the diameter of the aorta was measured and compared with those obtained by micro-CT. Results. Time-dependent signal enhancement in the aorta shows that the contrast agent has a long blood half-life of 6 hours, with a peak enhancement at 2 hours after injection. Injection of 100 μl ExiTron nano 12000 per 25 g mouse allows for effective visualization of the aorta. Micro-CT combined with contrast agent can monitor the changing process of the aorta in the mouse model of aortic aneurysm and dissection dynamically. The values of the diameter of the aortas obtained from the in vivo micro-CT imaging were compared with those obtained from histology and showed a significant correlation (R2 = 0.96). Conclusions. These data demonstrate that in vivo micro-CT is an accurate and feasible technique to detect aortic aneurysm or dissection in a mouse model, and the micro-CT technique using the innovative contrast agent ExiTron nano 12000 allows for monitoring various processes dynamically such as aortic remodeling in longitudinal studies.

Download Full-text

P25 Utrophin luciferase knock-in mouse model for in vivo assessment of drug efficacy in preclinical trials for utrophin upregulation

Neuromuscular Disorders ◽

10.1016/s0960-8966(10)70040-7 ◽

2010 ◽

Vol 20 ◽

pp. S12

Author(s):

R.J. Fairclough ◽

K.E. Davies

Keyword(s):

Mouse Model ◽

Drug Efficacy ◽

Preclinical Trials ◽

In Vivo Assessment

Download Full-text

Activity of Posaconazole against Pseudallescheria boydii: In Vitro and In Vivo Assays

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.47.4.1436-1438.2003 ◽

2003 ◽

Vol 47 (4) ◽

pp. 1436-1438 ◽

Cited By ~ 43

Author(s):

Gloria M. González ◽

Rolando Tijerina ◽

Laura K. Najvar ◽

Rosie Bocanegra ◽

Michael G. Rinaldi ◽

...

Keyword(s):

Mouse Model ◽

Vitro Activity ◽

In Vitro Activity ◽

Pseudallescheria Boydii ◽

In Vivo Assays ◽

Immunosuppressed Mouse

ABSTRACT Thirty isolates of Pseudallescheria boydii were tested to compare the in vitro activity of posaconazole with those of fluconazole and itraconazole, using NCCLS methods. Posaconazole was evaluated in an immunosuppressed mouse model of disseminated pseudallescheriasis. Posaconazole was more effective than itraconazole and as effective as fluconazole in preventing death and significantly reducing the CFU of P. boydii from tissues.

Download Full-text