更新于：2024-11-01

toxA

更新于：2024-11-01

基本信息

别名

toxA、Toxin A

简介

Precursor of a cytotoxin that targets and disrupts the colonic epithelium, inducing the host inflammatory and innate immune responses and resulting in diarrhea and pseudomembranous colitis (PubMed:20844489). TcdA and TcdB constitute the main toxins that mediate the pathology of C.difficile infection, an opportunistic pathogen that colonizes the colon when the normal gut microbiome is disrupted (PubMed:19252482, PubMed:20844489). Compared to TcdB, TcdA is less virulent and less important for inducing the host inflammatory and innate immune responses (PubMed:19252482). This form constitutes the precursor of the toxin: it enters into host cells and mediates autoprocessing to release the active toxin (Glucosyltransferase TcdA) into the host cytosol (By similarity). Targets colonic epithelia by binding to some receptor, and enters host cells via clathrin-mediated endocytosis (By similarity). Binding to LDLR, as well as carbohydrates and sulfated glycosaminoglycans on host cell surface contribute to entry into cells (PubMed:1670930, PubMed:31160825, PubMed:16622409). In contrast to TcdB, Frizzled receptors FZD1, FZD2 and FZD7 do not act as host receptors in the colonic epithelium for TcdA (PubMed:27680706). Once entered into host cells, acidification in the endosome promotes the membrane insertion of the translocation region and formation of a pore, leading to translocation of the GT44 and peptidase C80 domains across the endosomal membrane (By similarity). This activates the peptidase C80 domain and autocatalytic processing, releasing the N-terminal part (Glucosyltransferase TcdA), which constitutes the active part of the toxin, in the cytosol (PubMed:17334356, PubMed:19553670, PubMed:27571750). Active form of the toxin, which is released into the host cytosol following autoprocessing and inactivates small GTPases (PubMed:7775453, PubMed:24905543, PubMed:30622517, PubMed:22747490, PubMed:22267739). Acts by mediating monoglucosylation of small GTPases of the Rho family (Rac1, RhoA, RhoB, RhoC, Rap2A and Cdc42) in host cells at the conserved threonine residue located in the switch I region ('Thr-37/35'), using UDP-alpha-D-glucose as the sugar donor (PubMed:7775453, PubMed:24905543, PubMed:30622517, PubMed:22747490, PubMed:22267739). Monoglucosylation of host small GTPases completely prevents the recognition of the downstream effector, blocking the GTPases in their inactive form, leading to actin cytoskeleton disruption and cell death, resulting in the loss of colonic epithelial barrier function (PubMed:7775453). Also able to catalyze monoglucosylation of some members of the Ras family (H-Ras/HRAS, K-Ras/KRAS and N-Ras/NRAS), but with much less efficiency than with Rho proteins, suggesting that it does not act on Ras proteins in vivo (PubMed:30622517).

关联

项与 toxA 相关的药物

G03-52-01

靶点

toxA x toxB

作用机制

toxA抑制剂 [+1]

在研机构

Resilience Government Services, Inc.

原研机构

Resilience Government Services, Inc.

在研适应症-

非在研适应症-

最高研发阶段临床2期

首次获批国家/地区-

首次获批日期1800-01-20

9MW1411

靶点

toxA

作用机制

toxA抑制剂

在研机构

原研机构

在研适应症

非在研适应症

最高研发阶段临床2期

首次获批国家/地区-

首次获批日期1800-01-20

Cd-ISTAb

靶点

toxA x toxB

作用机制

toxA抑制剂 [+1]

在研机构

Integrated Biotherapeutics, Inc.

原研机构

Integrated Biotherapeutics, Inc.

在研适应症

艰难梭菌感染

非在研适应症-

最高研发阶段临床申请

首次获批国家/地区-

首次获批日期1800-01-20

项与 toxA 相关的临床试验

NCT05348993 / Active, not recruiting临床2期

A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety, Tolerability, Pharmacodynamics, and Immunogenicity of G03-52-01 in Adult Subjects

A Phase 2, randomized, double-blind, placebo-controlled single or repeat dose trial

开始日期2022-06-29

申办/合作机构

Resilience Government Services, Inc.

[+1]

CTR20212875 / Recruiting临床2期

9MW1411注射液联合抗菌药物治疗急性金黄色葡萄球菌皮肤及皮肤结构感染患者有效性和安全性的多中心、随机、双盲、安慰剂对照Ⅱ期临床研究

主要目的：评价9MW1411注射液联合抗菌药物治疗急性金黄色葡萄球菌皮肤及皮肤结构感染患者的有效性；次要目的：评价9MW1411注射液治疗急性金黄色葡萄球菌皮肤及皮肤结构感染患者的安全性；评价9MW1411注射液治疗急性金黄色葡萄球菌皮肤及皮肤结构感染患者的药代动力学特征；评价9MW1411注射液治疗急性金黄色葡萄球菌皮肤及皮肤结构感染患者的免疫原性。

开始日期2022-06-23

申办/合作机构

迈威（上海）生物科技股份有限公司

NCT05339802 / Unknown status临床2期

A Multicenter, Randomized, Double-blind, Placebo-controlled Phase II Clinical Study of the Efficacy and Safety of 9MW1411 Injection Combined With Antibiotics in Patients With Acute Staphylococcus Aureus Skin and Skin Structure Infection

In this study, a multicenter, randomized, double-blind, placebo-controlled trial design is used to evaluate the efficacy and safety of two doses of 9MW1411 injection in patients with ABSSSI caused by S. aureus.
The Recommended Phase 2 Dose (RP2D) of 9MW1411 injection for this placebo-controlled study is comprehensively selected based on the results of Phase I clinical trials and preclinical PK/PD analysis. Approximately 90 subjects with ABSSSI caused by S. aureus are planned to be enrolled, and the infection type and presence or absence of single S. aureus infection will be used as randomization stratification factors for all randomized subjects. They are randomized in a 1: 1: 1 ratio.

开始日期2022-02-16

申办/合作机构

迈威（上海）生物科技股份有限公司

100 项与 toxA 相关的临床结果

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100 项与 toxA 相关的转化医学

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0 项与 toxA 相关的专利（医药）

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1,213

项与 toxA 相关的文献（医药）

2024-11-01·3 Biotech

Comparative genomics of zoonotic pathogen Clostridioides difficile of animal origin to understand its diversity

Article

作者: Sharma, Rajeev Kumar ; Priyadharshini, Murugaiyan Latha Mala ; Manoharan, Seeralan ; Karthik, Kumaragurubaran ; Anbazhagan, Subbaiyan

Clostridioides difficile, a zoonotic pathogen causing enteric diseases in different animals and humans. A comprehensive study on the presence of toxin genes and antimicrobial resistance genes based on genome data of C. difficile in animals is scanty. In the present study, a total of 15 C. difficile isolates were recovered from dogs and isolates with toxin genes (D1, CD15 and CD26) along with two other non-toxigenic strains (CD28, CD32) were used for whole genome sequencing and comparative genomics. Sequence type-based clustering was noted in the whole genome phylogeny with 4 known multi-locus sequence typing (MLST) clades namely I, II, IV, and V and a cryptic clade. ST11 and ST54 were reported for the 2^nd time worldwide in dogs. Out of 109 genomes used in the study, 29 genomes were predicted with all four toxin genes (toxA, toxB, cdtA, cdtB) while 22 did not have any of the toxin genes. ST11 of MLST clade V had the maximum number of 46 genomes predicted with at least one toxin gene. Among the genomes sequenced in this study, CD26 had a maximum of 5 AMR genes (aac(6')-aph(2″), ant(6)-Ia, catP, erm(B)_18, and tet(M)_11) and CD15 was predicted with 2 AMR genes (aac(6')-aph(2″), erm(B)_18). Tetracycline resistance genes were predicted most in the ST11 genome. Of the 22 non-toxigenic strains, 9 genomes (ST48 = 5, ST3 = 2, ST109 = 1, ST15 = 1) were predicted with a minimum of one AMR gene. Pangenome analysis indicated that the Bpan value is 0.12 showing that C. difficile has an open pangenome structure. This indicates that the organism can evolve by the addition of new genes. This study reports the circulation of clinically important ST11 and multidrug-resistant non-toxigenic strains among animals.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13205-024-04102-7.

2024-09-03·Preparative Biochemistry & Biotechnology4区 · 工程技术

Effect of various light spectra on amino acids and pigment production of Arthrospira platensis using flat-plate photobioreactor

4区 · 工程技术

Article

作者: Sepasi Tehrani, Hessam ; Soltani, Neda ; Tayebati, Hanieh ; Pajoum Shariati, Farshid

Today, the use of nutrients derived from natural bioactive compounds application in the food, pharmaceutical, and cosmetic industries is on the increase. This paper aimed to evaluate the amino acids profile (essential and non-essential) and pigments composition (chlorophyll a, carotenoids, and phycocyanin) of Arthrospira platensis (a blue-green microalga) cultivation in a flat-plate photobioreactor under various types of light-emitting diodes (red: 620-680 nm, white: 380-780 nm, yellow: 570-600nm, blue: 445-480 nm). The maximum biomass concentration (604.96 mg L^-1) occurred when the red LED was applied for cultivation, and the minimum biomass concentration (279.39 mg L^-1) was obtained under blue LED. The sequence of pigments and amino acids concentrations (mg L^-1_{culture volume}) was approximately in accordance with the biomass productivity. It means the red light produces the maximum concentration of pigments (chlorophyll a: 5.42, carotenoids: 2.92, phycocyanin: 67.54 mg L^-1) and amino acids (essential amino acids: 110.47, nonessential amino acids: 179.10 mg L^-1). Nevertheless, when these values were measured in mg per g of dry weight, the utmost contents were observed in microalgal products cultivated under blue LED. These consequences are due to the highest cell productivity and the most extended length of cells that occurred under red and blue LEDs, respectively.

2024-09-01·Heliyon

Investigating the mildew and yeast in the bakeries of Abhar City, Iran

Article

作者: Kashi, Giti

The presence of mold and yeast in bread leads to contamination in bread. Cancer and estrogenic abnormalities in humans are among the diseases caused by fungal and mold mycotoxins in bread. Bread production waste was estimated at about 30 % in Iran country. A comprehensive and specific image study of the sanitary condition of bread and bakeries in Abhar city has not been done. The purpose of this study was to determine the contamination resulting in yeast and mildew on bread supplied in Abhar City bakeries, to examine the sanitary condition of bakeries, and to provide the food security of Iranians. As well as determining the impact of health status variables and the location of bakeries on mold and fungal contamination. This research was done in the bakeries of Abhar in the period of February 1, 2022 to July 1, 2022. Evaluation of mold and yeast load of 61 breads from 61 bakeries was done using sterile potato dextrose agar with Chloramphenicol plates. In order to check the hygiene status of the bakery environment, modified form of Article 13 with 56 items equal to 56 scores was completed. Variables such as baking soda, sodium dithionite, salt percentage, to evaluate mildew and yeast, and the sanitary condition of bakeries were analyzed. After evaluating health status, the score range was divided based on a 4-point Likert scale. All results were compared with the standard and contamination level of each restaurant. 31 of 60 samples (51.6 %) showed mold and yeast infection. 17 bakeries of the 61 bakeries surveyed (43 %) received 100 % points in the five sections (individual health of 14 items, food hygiene of 10 items, tools and equipment of 16 items, building sanitation of 16 items, and disinfection). 49 samples (80.3 %) of 61 breads evaluated by chemical standard such as amount of baking soda were favorable. Sixty samples (98.4 %) of 61 breads complied with the chemical standard of sodium dithionite. 5 samples (8.3 %) of the 61 breads had excess salt levels. 33 samples out of 61 tested (54.1 %) were infected with mold and yeast. Of these, 26 (78.7 %) belonged to serotypes producing toxin A. The bread quality in some bakeries in Abhar City is poor and infected with mold and yeast. Careful monitoring and monitoring of the health status of bakeries, along with training sessions for bakery staff, will lead to improved baking health.

项与 toxA 相关的新闻（医药）

2023-02-24

·生物制药小编

诺贝尔奖得主之死

此前，根据法新社消息，经过再度开馆验尸后，在1973年死亡的智利诗人兼诺贝尔文学奖得主巴勃罗·聂鲁达被发现并不是像70年代皮诺切特官方声称的因前列腺癌去世，而是因为存在“大量与人体不相容的肉毒杆菌”，确系此前猜测的那样遭毒杀身亡。熟悉这段历史的读者可能知道整个历史事件的来龙去脉，这里就不详细赘述了，感兴趣的读者可以自行查阅。只是为何要选取肉毒杆菌作为生物武器？这可能是因为肉毒杆菌分泌的A型肉毒毒素是已知天然毒素和化学毒剂中毒性最强的毒性物质，因此成为了帮凶。虽然在上世纪80-90年代逐步出现了更多的用途，但其致命性仍然值得敬畏。而时至今日，虽然目前肉毒毒素已经在医美行业中得到了广泛的应用，但仍然具有潜在可能致死的副作用，解决这些存在的潜在问题是目前肉毒毒素的应用方向，本文将就肉毒毒素的作用机制，开发前景，防范措施进行简单介绍。肉毒毒素的作用机制肉毒杆菌是一种生长在缺氧环境下的细菌，在罐头食品及密封腌渍食物中具有极强的生存能力，该菌种在繁殖过程中分泌肉毒毒素（BoNT）。所有BoNT都由通过二硫键连接的两条肽链组成，但在BoNT的每个亚型中发现的各种肽链的氨基酸序列存在显著差异。重链的分子量为100 k道尔顿，轻链的分子量为50 k道尔顿。由于氨基酸序列存在差异而导致的七种毒素血清型(A-G)传统上是按其抗原性来区分的。它们具有不同的三级结构和层序差异。BoNT通过切割神经激活所需的关键蛋白质来发挥作用。骨骼肌收缩的功能单位包括运动终板，它是运动神经元和肌纤维之间的连接点。当中枢神经系统内运动神经元的初始段产生的动作电位到达末端时，乙酰胆碱(ACh)从运动轴突的末端释放。然后，当结合并打开肌纤维上特定离子型受体(烟碱胆碱能受体)的ACh使突触后膜去极化时，肌纤维收缩。BoNT基本上阻断了ACh从运动终末的释放，因此，即使动作电位继续到达运动终板，骨骼肌也不能收缩。首先，重链的受体结合域与细胞表面的多聚唾液酸神经节苷脂(PSGs)结合。随后，毒素通过与另一种表面受体(突触结合蛋白(Syt)或糖基化Sv2)结合而被内化。内化后，毒素会驻留在突触小泡内。然后，囊泡被H+离子酸化后通过囊泡质子泵，从而激活囊泡膜中的ACh转运蛋白，其输入并浓缩囊泡内的胞质ACh。在这个阶段，在没有BoNT的情况下，囊泡准备与突触前膜融合，并将ACh释放到突触间隙中。然而，BoNT会干扰其后的释放步骤。首先，轻链（LC）从囊泡内部“易位”到细胞质，这是由重链的N末端(易位结构域)促成的。轻链保持无活性，同时仍与毒素的其余部分结合。易位后，轻链通过裂解酶如热休克蛋白90 (hsp90)和硫氧还蛋白还原酶-硫氧还蛋白系统(TrxR-Trx)的作用被释放。游离且具有活性的轻链在此时能够切割和灭活各种蛋白质，如VAMP、SNAP25和突触融合蛋白，而这些蛋白质则是乙酰胆碱的释放是必要的。（如下图所示）一旦切割成功，这意味着乙酰胆碱囊泡不能与胞内细胞膜结合，阻止细胞释放神经递质囊泡。这会阻断神经信号，导致瘫痪。虽然不同的毒素类型都针对SNARE家族成员，但不同的毒素类型针对不同的SNARE家族成员。其中BoNT/A、BoNT/B、BoNT/E和BoNT/F会导致人类和动物肉毒中毒，而BoNT/C和BoNT/D只会导致家畜疾病。此外，现有的毒素类型可以重组，创造“杂交”(嵌合，嵌合)类型。例如BoNT/CD, BoNT/DC和BoNT/FA，第一个字母表示轻链类型，后者表示重链类型。图：A型肉毒杆菌毒素的示意图和晶体结构当人们食入和吸收这种毒素后，神经系统将遭到破坏，出现眼睑下垂、复视、斜视、吞咽困难、头晕、呼吸困难和肌肉乏力等症状，严重者可因呼吸麻痹而死亡。一般估计致死量为：静脉或肌肉注射的致死剂量0.09~0.15μg，吸入的致死剂量0.70~1.0μg，口服的致死剂量70μg。而除了历史上较为有名的暗杀行动之外，（例如CIA试图暗杀卡斯特罗的多次都用到了肉毒素）一些过期的罐头食品的食用也可能导致中毒。不过在进入19世纪末期后，除了生物武器这一罪恶的用途之外，BoNT在医学和美容上的应用得到了出乎意料的拓宽。医学上的适用范围在医学和美容方面，由于可以抑制胆碱能神经末梢释放乙酰胆碱，导致肌肉松弛型麻痹，因此一些神经相关疾病，是肉毒杆菌的适用范围。BoNT于1989年由美国FDA首次批准用于治疗斜视。自那以后，对肉毒杆菌毒素的研究激增，导致了适应症范围越来越广的新配方的增加。迄今为止，BoNT已被神经科医师和美容医师广泛使用。随着BoNT的治疗适应症数量的迅速增加，第一个商品名“oculinum”在进入市场的头两年内改名为“Botox ”。近年来，泌尿科医生和疼痛专家越来越多地将BoNT用于各种新的适应症。例如治疗膀胱过度活动（尿失禁等），偏头痛等疾病。而在过去的几年中，已经开发了许多创新的BoNT配方。除了自然衍生的产品，合成的、基因工程的产品现在也可以获得。但是可获得的制剂的药理学特征存在一些差异，这一点值得审查。总的来说，有超过六种不同的配方被批准用于临床，还有更多正在研发中。BoNT的开发前景由于BoNT本身具有强大的副作用（甚至可能致死），因此一些现有的开发手段将致力于解决BoNT的不足之处，并拓宽其用途。例如，有一种开发方法是从两种不同的BoNT血清型或亚型中设计嵌合蛋白，2008年发表的一篇文献开发了BoNT/EA和BoNT/AE，两种嵌合蛋白都保留了基本的BoNT功能，但瘫痪时间不同，并且效力低于任何一种亲本毒素。发现重组毒素切割SNAP-25，AE嵌合体的恢复需要37天。还发现BoNT/EA可阻断辣椒素诱发的促炎降钙素基因相关肽(CGRP)的释放，因此这种肉毒毒素可能还是治疗偏头痛型头痛的潜在方法。此外还有增强毒力方面的开发，例如2012年发表的一篇文献指出BoNT/BA嵌合体的毒性是BoNT/A的两倍，是BoNT/AB的20倍。发现BoNT/AB嵌合体比亲代BoNT/A显著切割更多的SNAP-25，并导致更持久的瘫痪。BoNT/AB嵌合体的效力是重组BoNT/A的8.4倍又例如使用重组DNA技术，也可以通过改变BoNT氨基酸序列来修饰BoNT的活性。根据临床需要，修饰的BoNT可能靶向其他受体蛋白。通过观察BoNTs中自然发生的点突变导致的结构和功能变化，说明了这种方法的可行性。在2011年，就有研究人员鉴定出一种具有LC突变的重组BoNT/C1，该株则不能切割SNAP-25。此前韩国成均馆大学的研究团队曾经开发过一种重组肽C肉毒杆菌神经毒素A-1型(BoNT/A1)可作为重组肽的阻断材料，用于标记神经系统或治疗各种神经元疾病。伊朗阿扎德大学的研究人员则致力于将其开发成一种无需注射的渗透型药物BoNT/A(1–448)，以此减少BoNT可能致死的副作用。预防措施考虑到肉毒素的致命性，一些可能的生物恐怖主义行为值得担忧，例如美国或英国确实在历史上使用过肉毒杆菌作为生物武器，并不能排除现在还在开发的可能，尤其是1973年至今技术可能有所迭代。此外，因为某些事故意外中毒也值得担忧，那么肉毒素的预防措施能够做到未雨绸缪吗？一般来说，接种疫苗是预防肉毒杆菌神经毒素中毒的有效方法。在以前的研究中，已知会导致人类肉毒中毒的BoNT血清型A、B、E和F的重组Hc抗原被证明是高度免疫原性和有效的，并且可以用作针对肉毒中毒的单价疫苗。2022年4月来自我国的研发团队发表的一篇文献指出，该研究团队在此基础上开发了一种四价肉毒杆菌疫苗(TBV)。TBV对小鼠各种BoNT均有较强的保护效力，并在4℃保存两年后仍保持有效，表明该制剂稳定高效。吸附实验还表明，铝佐剂能很好地吸附储存2年后的抗原。参考来源：Kim HR, Jung Y, Shin J, Park M, Kweon DH, Ban C. Neuron-recognizable characteristics of peptides recombined using a neuronal binding domain of botulinum neurotoxin. Sci Rep. 2022 Mar 23;12(1):4980. doi: 10.1038/s41598-022-09145-5. PMID: 35322139; PMCID: PMC8943039.Saffarian P, Peerayeh SN, Amani J, Ebrahimi F, Sedighianrad H, Halabian R, Imani Fooladi AA. Expression and purification of recombinant TAT-BoNT/A(1-448) under denaturing and native conditions. Bioengineered. 2016 Nov;7(6):478-483. doi: 10.1080/21655979.2016.1201252. Epub 2016 Aug 26. Erratum for: Addendum to: Saffarian P., Peerayeh S. N., Amani J., Ebrahimi F., Sedighian H., Halabian R., Fooladi A. A., TAT-BoNT/A(1–448), a novel fusion protein as a therapeutic agent: analysis of transcutaneous delivery and enzyme activity. Applied Microbiology and Biotechnology, 2016. 100(6): p. 2785-95. doi: 10.1007/s00253-015-7240-7. PMID: 27566060; PMCID: PMC5241812.Choudhury S, Baker MR, Chatterjee S, Kumar H. Botulinum Toxin: An Update on Pharmacology and Newer Products in Development. Toxins (Basel). 2021 Jan 14;13(1):58. doi: 10.3390/toxins13010058. PMID: 33466571; PMCID: PMC7828686.Shi DY, Liu FJ, Li ZY, Mao YY, Lu JS, Wang R, Pang XB, Yu YZ, Yang ZX. Development and evaluation of a tetravalent botulinum vaccine. Hum Vaccin Immunother. 2022 Nov 30;18(5):2048621. doi: 10.1080/21645515.2022.2048621. Epub 2022 Apr 18. PMID: 35435814; PMCID: PMC9196761.