通过路径工程生成具有细胞毒性的链球菌体,并深入了解它们的生物合成
Fei Xiao1, Mingyuan Xu1, Yongmeng Cheng1
1Key Laboratory of Marine Drugs, Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao, China.
Applied and environmental microbiology
|February 2, 2024
概括
研究人员探索了链状碳化合物的生物合成,这是一种抗瘤内碳化合物 (ICZs) 类. 他们发现了新的ICZ衍生物,并提出了一种生物合成途径,增强了药物发现潜力.
科学领域:
- 微生物学和天然产品化学
- 专注于具有制药潜力的微生物二次代谢物.
背景情况:
- 印洛卡巴醇 (ICZs) 是一种重要的抗瘤药物类别,在临床试验中有几种类似物.
- 链状碳类,ICZs的一个子类,具有独特的N-糖链接,但它们的生物合成途径在很大程度上是未知的.
- 了解ICZ生物合成对于发现新的抗癌药物候选人至关重要.
研究的目的:
- 为了阐明链状碳素菌的生物合成途径.
- 识别具有潜在细胞毒性活动的新型链状碳素衍生物.
- 通过合成生物学方法来增强链球菌素的生产.
主要方法:
- 在Streptomyces菌株中,对稳体生物合成基因集群 (spc) 的基因操纵.
- 改造基因集群的异质表达以产生新的化合物.
- 使用光谱学方法,循环二元化和X射线晶体学进行结构阐明.
- 对人类癌细胞系的细胞毒性测定 (HCT-116和Huh 7).
- 双基因淘汰实验,以提出生物合成途径.
- 酶过度表达以改善化合物生产.
主要成果:
- 成功生成了两种新的链状碳素衍生物 (1和3) 和三种已知的ICZ (2,4和5).
- 化合物1-4对HCT-116细胞表现出中度细胞毒性;化合物3和4对Huh 7细胞有效.
- 在基因研究的基础上,提出了一种可能的链状碳素酶生物合成途径.
- 关键酶的过度表达导致了链状碳素酶1和3的产生增加了1.5-2.5倍.
结论:
- 这项研究阐明了链状碳素菌的生物合成,丰富了ICZ化合物的结构多样性.
- 鉴定到的新型衍生物和阐明的途径有助于发现新的链球菌.
- 这项工作为合成生物学策略提供了基础,以开发基于ICZ的新型抗癌药物.
更多相关视频
相关概念视频
Intracellular Movement of Viruses and Bacteria
3.0K
Intracellular bacteria and viruses often comprise a group of highly infectious pathogens that can cause several diseases. Bacterial pathogens include those belonging to the genus Rickettsia responsible for conditions such as rocky mountain spotted fever and the Mediterranean spotted fever; Chlamydia, a genus responsible for a sexually transmitted disease; Coxiella burnetii, an agent responsible for Q fever. Viral pathogens include vaccinia—a poxvirus, and herpes simplex virus—a...
3.0K
Microbial Morphologies
4.8K
Bacterial and archaeal cells exhibit remarkable diversity in shape and structure, critical in their adaptability and functionality. Among bacteria, the most commonly observed shapes include cocci and bacilli. Cocci are spherical and may exist singly or in groupings such as pairs (diplococci), chains (streptococci), clusters (staphylococci), or tetrads. Bacilli, in contrast, are rod-shaped and can also occur as single cells, in pairs, or chains, depending on their environmental and genetic...
4.8K
Bacterial Phylum Planctomycetes
564
Planctomycetes are a group of morphologically distinct bacteria predominantly classified into two orders: Planctomycetales and Brocadiales. These gram-negative bacteria exhibit unique features, including division by budding and the presence of stalks or appendages. Their cells are often found in rosette arrangements, and they are notable for possessing an S-layer in their cell envelope, which is relatively uncommon among bacteria. Additionally, Planctomycetes frequently exhibit intracellular...
564
Bacterial Phylum Actinobacteria
854
Coryneform bacteria are gram-positive, aerobic, nonmotile rods that exhibit irregular, club-shaped, or V-shaped arrangements. Their V-shape results from snapping division, where the inner cell wall layer forms the cross-wall, while the outer layer remains intact until it ruptures on one side, causing the daughter cells to bend away.The primary genera are Corynebacterium and Arthrobacter. Corynebacterium includes diverse species, ranging from saprophytes to pathogens like Corynebacterium...
854
Viral Replication: Lytic Cycle
3.0K
Bacteriophages, or phages, are viruses that specifically infect bacteria. Among them, T-even bacteriophages, such as T4, exhibit a well-characterized lytic replication cycle in Escherichia coli (E. coli). This process ensures the rapid proliferation of the virus while ultimately leading to the destruction of the bacterial host.Attachment and DNA InjectionThe infection process begins with the recognition and binding of the T4 phage to the E. coli cell surface. Tail fibers of the phage...
3.0K
Colonisation of Pathogens
77
Pathogen colonization of host tissues is a critical step in the development of infectious diseases. Various pathogenic microorganisms, including bacteria, fungi, viruses, and protozoa, have evolved complex strategies to attach to, invade, and persist within host environments. These mechanisms enable pathogens to establish infections, evade immune responses, and resist antimicrobial treatments.Attachment to Host CellsIn bacteria, colonization typically begins with adherence to host epithelial...
77


