广泛的功能丧失突变意味着对新的或重新设计的抗结核药物具有先前存在的耐药性
Derek Conkle-Gutierrez1, Bria M Gorman1, Nachiket Thosar1
1Laboratory for Pathogenesis of Clinical Drug Resistance and Persistence, San Diego State University, San Diego, CA, USA.
概括
结核病中已经存在的抗药性突变很常见,甚至在使用新药之前. 包括结构变异在内的全面的基因组分析对于识别这些突变和预防未来的耐药性至关重要.
科学领域:
- 基因组学就是基因组学.
- 微生物学 微生物学
- 药物发现 药物发现 药物发现
背景情况:
- 针对多药耐药结核病批准的五种新药或重用药物 (NRD) 正面临新出现的耐药性.
- 对这些NRD的耐药性出现的速度比预期的更快,可能是由于先前存在的耐药性在原始菌株中.
- 关于快速耐药性出现的先前研究主要集中在短遗传变异上.
研究的目的:
- 综合研究结核病中对新药或转型药物 (NRD) 耐药性的快速出现.
- 利用 de novo组装的基因组,并系统地包括结构变异 (SV) 和异质性.
- 识别新的耐药性标志物,并为防止未来药物开发中预先存在的耐药性奠定基础.
主要方法:
- 进行了系统的文献审查,确定了13个基因的313个NRD耐药变体.
- 分析了409个不同的临床结核病分离物 (收集的预编程药物使用) 对于这些13个基因的常规,结构和异质变异.
- 在106个分离物中使用了新的基因组组装来全面评估遗传变异.
主要成果:
- 确定了72种假定NRD耐药变体,包括5种先前报告的和67种新型的.
- 观察到各种类型的突变:促进子突变,框架转移,结构变异 (SV) 和异质框架转移/SV.
- 德拉曼尼德和普雷托曼尼德耐药性突变是最普遍的 (48/409个单独体),而线索利德耐药性突变是最不常见的 (8/409个单独体).
结论:
- 预先存在的突变对至少一个NRD产生抗性是非常普遍的 (21%的分离物).
- 这些突变主要是参与前药物激活和排泄调节的基因中的功能丧失变异.
- 综合性评估方法,特别是对SV和异质性的综合性评估方法,可以帮助减轻早期药物开发阶段先前存在的耐药性风险.
相关概念视频
Pulmonary Tuberculosis I
220
Tuberculosis, often called TB, is a contagious illness primarily caused by Mycobacterium tuberculosis. It mainly affects the lung parenchyma but can also impact other body parts.
Causative Organism
The primary infectious agent causing tuberculosis is Mycobacterium tuberculosis, a slow-growing, acid-fast, aerobic rod that exhibits sensitivity to heat and ultraviolet light. Instances of Mycobacterium bovis and Mycobacterium avium contributing to the development of TB infection are rare.
Mode of...
Causative Organism
The primary infectious agent causing tuberculosis is Mycobacterium tuberculosis, a slow-growing, acid-fast, aerobic rod that exhibits sensitivity to heat and ultraviolet light. Instances of Mycobacterium bovis and Mycobacterium avium contributing to the development of TB infection are rare.
Mode of...
220
Pulmonary Tuberculosis V
170
Medical management of tuberculosis (TB) patients involves a comprehensive approach that includes diagnosis, treatment, and monitoring. The specific strategies can vary depending on the type of tuberculosis (latent or active), the patient's overall health status, and other considerations.
Latent tuberculosis infection occurs when TB bacteria are present in a person's body, but are not causing illness or symptoms. It is not contagious, and preventive treatment is crucial to avoid the...
Latent tuberculosis infection occurs when TB bacteria are present in a person's body, but are not causing illness or symptoms. It is not contagious, and preventive treatment is crucial to avoid the...
170
Development of Antibiotic Resistance
Antibiotic resistance is a major public health concern that arises when bacteria evolve mechanisms to withstand the effects of antibiotic treatments. This resistance can be intrinsic, acquired through genetic mutations, or transferred between bacteria via horizontal gene transfer. The development of antibiotic resistance poses significant challenges in treating bacterial infections and necessitates ongoing research to develop new therapeutic strategies.Intrinsic resistance occurs when bacterial...
Pulmonary Tuberculosis II
212
Tuberculosis, or TB, is a bacterial infectious disease caused by Mycobacterium tuberculosis. While its primary impact is on the lungs, leading to pulmonary tuberculosis, it can also affect various other organs, a condition referred to as extrapulmonary tuberculosis.
Here is a detailed explanation of its pathophysiology:
Transmission: The process begins when a person inhales droplet nuclei containing M. tuberculosis. These are typically released into the air when an individual with pulmonary or...
Here is a detailed explanation of its pathophysiology:
Transmission: The process begins when a person inhales droplet nuclei containing M. tuberculosis. These are typically released into the air when an individual with pulmonary or...
212
Pulmonary Tuberculosis III
307
Tuberculosis (TB) is a contagious infection primarily affecting the lung parenchyma but which can also affect other body parts. TB can be classified based on disease development, presentation, and the affected anatomical site.
The first classification is based on the development of the disease, and it includes the following categories:
The first classification is based on the development of the disease, and it includes the following categories:
307
Pulmonary Tuberculosis IV
134
Tuberculosis, more commonly referred to as TB, is an infectious disease stemming from Mycobacterium tuberculosis. While it primarily impacts the lungs, TB can also affect other body areas. Given its severity and global impact, timely and accurate diagnosis is crucial for controlling its spread and improving patient outcomes.
Several diagnostic approaches are used to detect TB. The conventional method is the Tuberculin Skin Test (TST), also known as the Mantoux test. However, this method has...
Several diagnostic approaches are used to detect TB. The conventional method is the Tuberculin Skin Test (TST), also known as the Mantoux test. However, this method has...
134


