A Multiple Arm, Multiple Stage, Phase 2, OL, Randomized, Controlled Trial to Evaluate 4 Treatment Regimens of SQ109, Increased Doses of Rifampicin, and Moxifloxacin in Adults With Newly Diagnosed, Smear-positive Pulmonary Tuberculosis

This study is a multiple-arm, multiple-stage (MAMS), phase 2, open label, randomized, controlled clinical trial that will compare the efficacy and safety of four experimental four drug regimens with a standard control regimen in patients with smear positive, pulmonary tuberculosis (TB). Patients will be randomly allocated to the control or one of the four experimental regimens in the ratio 2:1:1:1:1. Experimental regimens will be given for 12 weeks. Thereafter, participants in the experimental arms will receive continuation phase treatment for 14 weeks containing standard-dose rifampicin and isoniazid. All participants will receive 25 mg of vitamin B6 (pyridoxine) with every dose of INH to prevent INH-related neuropathy. Interim analyses will be conducted during the trial for efficacy, with the aim of identifying experimental arms that perform below a pre-specified efficacy threshold; these arms will then be stopped from further recruitment.
Following the first scheduled interim analysis on March 3rd, the Trial Steering Committee (TSC) followed a recommendation of the independent data monitoring committee (IDMC) and has stopped the enrolment into two of the arms in the MAMS-TB trial: HRZQ and HR20ZQ, based on these arms not meeting the pre-specified gain in efficacy over control. Importantly, there was no safety concern that prompted stopping recruitment to these arms. They recommended that recruitment to arm 2 (HRZQ) and 3 (HR20ZQ) be terminated as there was insufficient evidence that these regimens could shorten treatment. Importantly, there was no evidence that either arm was inferior to standard treatment (the control arm) with regards to efficacy. There was, however, sufficient evidence that the other intervention arms HR35ZE and HR20ZM could shorten treatment to continue enrolling patients.

开始日期2013-04-01

申办/合作机构

Ludwig-Maximilians-Universität München

[+4]

PACTR201205000383208 / Unknown status临床2期IIT

A multiple arm, multiple stage (MAMS), phase 2, open label, randomized, controlled clinical trial to evaluate four treatment regimens including SQ109, two increased doses of rifampicin, and moxifloxacin in adult subjects with newly diagnosed, smear¿positive pulmonary tuberculosis

开始日期2013-01-11

申办/合作机构-

NCT01252108 / Withdrawn临床2期

Phase 2A Open-label Study to Evaluate Safety, Tolerability, and Antimicrobial Activity of Single, Daily Doses of SQ109 in Urea Breath Test Positive Volunteers

Helicobacter pylori infection of the gastric epithelium is the most common bacterial infection worldwide. Its global prevalence is estimated at 50%, though the burden falls disproportionately on the developing world, where the prevalence in some areas is 80%. H. pylori infection is generally acquired during childhood, and without specific antibiotic treatment can persist for life. The infection is generally clinically asymptomatic during childhood, and even in adulthood 80-90% of infected individuals will remain asymptomatic (although they may transmit the bacteria).
SQ109 is a new, small molecule antibiotic with characteristics that make it particularly attractive to evaluate against H. pylori. In brief, SQ109 is orally bioavailable, acid-stable, has in vitro activity against H. pylori and achieves high intracellular concentration (which may be important to effect bacterial eradication).
Based on the antimicrobial activity and clinical safety, SQ109 will be evaluated in this clinical trial to assess safety and antimicrobial activity in adults infected with H. pylori. Data from this study will help determine whether larger safety and efficacy studies in individuals with H. pylori-associated duodenal ulcer disease are warranted.

开始日期2012-03-01

申办/合作机构

Sequella, Inc.

100 项与 SQ-109 相关的临床结果

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100 项与 SQ-109 相关的转化医学

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100 项与 SQ-109 相关的专利（医药）

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101

项与 SQ-109 相关的文献（医药）

2024-10-16·mBio

Allosteric coupling of substrate binding and proton translocation in MmpL3 transporter from Mycobacterium tuberculosis

Article

作者: Jackson, Mary ; Yang, Lixinhao ; Gumbart, James C. ; Grzegorzewicz, Anna E. ; Li, Wei ; Zgurskaya, Helen I. ; Babii, Svitlana

ABSTRACT Infections caused by Mycobacterium spp. are very challenging to treat, and multidrug-resistant strains rapidly spread in human populations. Major contributing factors include the unique physiological features of these bacteria, drug efflux, and the low permeability barrier of their outer membrane. Here, we focus on MmpL3 from Mycobacterium tuberculosis , an essential inner membrane transporter of the resistance–nodulation–division superfamily required for the translocation of mycolic acids in the form of trehalose monomycolates (TMM) from the cytoplasm or plasma membrane to the periplasm or outer membrane. The MmpL3-dependent transport of TMM is essential for the growth of M. tuberculosis in vitro , inside macrophages, and in M. tuberculosis- infected mice. MmpL3 is also a validated target for several recently identified anti-mycobacterial agents. In this study, we reconstituted the lipid transport activity of the purified MmpL3 using a two-lipid vesicle system and established the ability of MmpL3 to actively extract phospholipids from the outer leaflet of a lipid bilayer. In contrast, we found that MmpL3 lacks the ability to translocate the same phospholipid substrate across the plasma membrane indicating that it is not an energy-dependent flippase. The lipid extraction activity was modulated by substitutions in critical charged and polar residues of the periplasmic substrate-binding pocket of MmpL3, coupled to the proton transfer activity of MmpL3 and inhibited by a small molecule inhibitor SQ109. Based on the results, we propose a mechanism of allosteric coupling wherein substrate translocation by MmpL3 is coupled to the energy provided by the downhill transfer of protons. The reconstituted activities will facilitate understanding the mechanism of MmpL3-dependent transport of lipids and the discovery of new therapeutic options for Mycobacterium spp. infections. IMPORTANCE MmpL3 from Mycobacterium tuberculosis is an essential transporter involved in the assembly of the mycobacterial outer membrane. It is also an important target in undergoing efforts to discover new anti-tuberculosis drugs effective against multidrug-resistant strains spreading in human populations. The recent breakthrough structural studies uncovered features of MmpL3 that suggested a possible lipid transport mechanism. In this study, we reconstituted and characterized the lipid transport activity of MmpL3 and demonstrated that this activity is blocked by MmpL3 inhibitors and substrate mimics. We further uncovered the mechanism of how the binding of a substrate in the periplasmic domain is communicated to the transmembrane proton relay of MmpL3. The uncovered mechanism and the developed assays provide new opportunities for mechanistic analyses of MmpL3 function and its inhibition.

2024-09-13·ACS Infectious Diseases

The Tuberculosis Drug Candidate SQ109 and Its Analogs Have Multistage Activity against Plasmodium falciparum

Article

作者: Adewole, Feyisola ; Koekemoer, Lizette L. ; Ko, Jihee ; Tshabalala, Sizwe ; Birkholtz, Lyn-Marié ; van der Watt, Mariette E. ; Njoroge, Mathew ; Onajole, Oluseye K. ; Malwal, Satish R. ; Turcu, Andreea L. ; van der Watt, Mariëtte E ; Stampolaki, Marianna ; Mazurek, Ben ; Watson, Savannah J. ; Theron, Anjo ; Naude, Mariska ; Sadowska, Katie ; Oldfield, Eric ; Perez-Lozano, Pilar ; van der Watt, Mariëtte E. ; Watson, Savannah J ; Chibale, Kelly ; Reader, Janette ; Vazquez, Santiago ; Kolocouris, Antonios ; Singh, Davinder ; Birkholtz, Lyn-Marie ; Erlank, Erica

Toward repositioning the antitubercular clinical candidate SQ109 as an antimalarial, analogs were investigated for structure-activity relationships for activity against asexual blood stages of the human malaria parasite Plasmodium falciparum pathogenic forms, as well as transmissible, sexual stage gametocytes. We show that equipotent activity (IC₅₀) in the 100-300 nM range could be attained for both asexual and sexual stages, with the activity of most compounds retained against a multidrug-resistant strain. The multistage activity profile relies on high lipophilicity ascribed to the adamantane headgroup, and antiplasmodial activity is critically dependent on the diamine linker. Frontrunner compounds showed conserved activity against genetically diverse southern African clinical isolates. We additionally validated that this series could block transmission to mosquitoes, marking these compounds as novel chemotypes with multistage antiplasmodial activity.

2024-03-26·ACS Omega

Novel Inhibitors to MmpL3 Transporter of Mycobacterium tuberculosis by Structure-Based High-Throughput Virtual Screening and Molecular Dynamics Simulations

Article

作者: Paradis, Nicholas J. ; Choksi, Hetanshi ; Wu, Chun ; Carbone, Justin ; Bui-Linh, Candice ; Bennett, Lucas

Tuberculosis (TB)-causing bacterium Mycobacterium tuberculosis (Mtb) utilizes mycolic acids for building the mycobacterial cell wall, which is critical in providing defense against external factors and resisting antibiotic action. MmpL3 is a secondary resistance nodulation division transporter that facilitates the coupled transport of mycolic acid precursor into the periplasm using the proton motive force, thus making it an attractive drug target for TB infection. In 2019, X-ray crystal structures of MmpL3 from M. smegmatis were solved with a promising inhibitor SQ109, which showed promise against drug-resistant TB in Phase II clinical trials. Still, there is a pressing need to discover more effective MmpL3 inhibitors to counteract rising antibiotic resistance. In this study, structure-based high-throughput virtual screening combined with molecular dynamics (MD) simulations identified potential novel MmpL3 inhibitors. Approximately 17 million compounds from the ZINC15 database were screened against the SQ109 binding site on the MmpL3 protein using drug property filters and glide XP docking scores. From this, the top nine compounds and the MmpL3-SQ109 crystal complex structure each underwent 2 × 200 ns MD simulations to probe the inhibitor binding energetics to MmpL3. Four of the nine compounds exhibited stable binding properties and favorable drug properties, suggesting these four compounds could be potential novel inhibitors of MmpL3 for M. tuberculosis.

项与 SQ-109 相关的新闻（医药）

2023-03-24

·CPHI制药在线

结核防治日 | 谈谈抗结核药物靶点研究新进展

关注并星标CPHI制药在线今年3月24日是第28个世界防治结核病日，今年的主题是："你我共同努力终结结核流行"。结核病（tuberculosis，TB）是由结核分枝杆菌（mycobacterium tuberculosis，MTB）引起的一种慢性致死性疾病，近些年来，由于抗结核药物的大量使用，抗结核作用位点的突变，耐多药结核病（MDR-TB）和广泛耐药结核病（XDR-TB）成为控制和治疗结核病的重大挑战。链霉素(streptomycin，SM)和对氨基水杨酸(p-amino salicylic acid，PAS) 是最早被发现并用于治疗TB的药物。随后，异烟肼(INH)的出现形成了" INH+SM+PAS"的三联疗法，基于患者的药源和耐受性，其中的PAS可选用氨硫脲(TB1)或乙胺丁醇(EMB)替换。1965年利福平(RIF)开始应用于临床后，相关研究发现"INH+RIF"可将治疗疗程减短到9个月，再进一步与吡嗪酰胺(PZA)结合使用能够使疗程减短至半年。此后，相关研究一直没有研发出应用于TB治疗的全新结构药物。近几十年来仅有强生公司的新型结核分枝杆菌ATP合酶抑制剂贝达喹啉（bedaquiline）和日本大冢公司的德拉马尼（delamanid）两种抗结核药物被批准上市，而目前已有耐药菌株出现及引起副作用的报道。因此，寻找新的抗结核药物作用靶点，开发新型抗结核药物迫在眉睫。（相关阅读：《新型抗结核药物的研究进展》）结核病的防治和新药研发首先需要发现和阐明其致病菌关键生理活动的分子机制。其中，结核分枝杆菌的细胞壁合成过程、DNA/RNA合成和能量代谢过程被认为是理想突破口，许多抗结核药物和在研药物均作用于这些重要生理途径。与细胞壁有关的药物靶点结核杆菌的细胞壁具有独特的结构和组成，是病原体抵抗环境压力，免受抗生素杀伤和逃避宿主免疫反应的天然屏障。其结构和组成与革兰氏阳性/阴性细菌以及真菌都存在显著差异，结核分枝杆菌细胞壁组分肽聚糖(peptidoglycan, PG)、阿拉伯半乳聚糖(arabinogalactan, AG)、分枝菌酸(mycolic acid, MA)、脂阿拉伯甘露聚糖(lipoarabinomannan,LAM)等均是结构复杂的分子，其合成、运输、组装、调控等需要一系列酶和转运膜蛋白参与完成。破坏细胞壁的完整性不仅有助于杀菌药物的进入，还会严重地影响病原体的生存，故细胞壁合成通路中的关键蛋白被公认为是很好的药物靶标。 ①DprE(decaprenylphosphoryl-D-ribose 2'-epimerase)。DprE是由DprE1和DprE2构成的异二聚体，在D-核糖向D-阿拉伯呋喃糖(DPA)的转化中起重要作用，而DPA是合成细胞壁阿拉伯聚糖的唯一前体。目前研发的抑制剂主要针对DprE1，包括苯并噻嗪酮类、氟喹诺酮类和氮杂吲哚类，其中氮杂吲哚衍生物TBA-7371处于临床试验的第一阶段。 ②分枝杆菌膜蛋3(Mmp L3)。Mmp L3主要参与Mtb的脂质运输、聚合和机体免疫调节等功能，是近期发现的一类治疗药物靶点。到目前为止，大约有8类不同分子构型的具有抗菌活性的MmpL3抑制剂被发现，其中乙二胺类的SQ109已处于2b-3期临床试验阶段。该小分子对耐药菌株有很好的杀菌效果，具有极低的耐药突变率，有望成为新的抗结核治疗药物。 ③L-鼠李糖合成相关酶。L-鼠李糖连接细胞壁肽聚糖和阿拉伯半乳聚糖（AG）两种组分，通过抑制其合成，可以影响MTB细胞壁的正常合成及生存。由于人体内不存在L-鼠李糖，所以L-鼠李糖合成中相关酶可以作为具有较好选择性的药物靶点。L-鼠李糖的合成主要涉及4种酶促反应，参与反应的4种酶分别为葡萄糖-1-磷酸脱氧胸苷转移酶（RmlA）、dTDP-D-葡萄糖-4,6-脱水酶（RmlB）、dTDP-4-酮基-6-脱氧葡萄糖差向异构酶（RmlC）和 dTDP-4-酮-鼠李糖还原酶（RmlD）。其中Rml C因其结构的特殊和底物的高特异性，以及对辅酶因子无依赖性而在研究领域受到广泛关注，但目前尚无相关的抑制剂上市。 ④阿拉伯糖基转移酶。细胞壁阿拉伯糖基转移酶EmbA、EmbB和EmbC均是参与细胞壁阿拉伯聚糖合成的阿拉伯糖基转移酶，属于糖基转移酶超家族GT-C中的GT-53家族。其中，EmbA和EmbB参与阿拉伯半乳聚糖AG的合成，而EmbC参与脂阿拉伯甘露聚糖LAM的合成。Emb蛋白均是利用D-阿拉伯呋喃糖(DPA)作为阿拉伯糖供体，将阿拉伯单糖转移至特定的阿拉伯聚糖受体上，完成阿拉伯聚糖的延伸或者分枝。Emb蛋白的活性测试表明，乙胺丁醇可以抑制其活性，因而是这些蛋白的直接作用靶点。研究表明，结核杆菌中的Emb蛋白均是无法敲除的关键蛋白，而一线药物乙胺丁醇的临床耐药突变大多发生在Emb蛋白上，尤其集中在EmbB蛋白。 ⑤烯酰基载体蛋白还原酶。烯酰基载体蛋白还原酶(Inh A)在细胞壁脂肪酸合成方面发挥着重要作用，是一线药物异烟肼(INH)的一个关键作用靶点。INH属于一类前体药物，依赖于KatG酶将其激活，而KatG的基因突变会阻断该激活途径并导致耐药。因此现在许多研究聚焦于Inh A的"直接抑制剂"。三氯生(TCS)属于一类广谱抗生素，可对Inh A造成可逆、温和的抑制。 ⑥D-丙氨酸-D-丙氨酸连接酶A(D-Alanyl-D-alanine ligase A，DdlA)能在ATP的介导下促进D-丙氨酸(Ala)分子的二聚化，获得D-丙氨酰-D-Ala。其产物与肽聚糖(PG)的五肽生物合成相关，能显著影响Mtb细胞壁的正常功能。D-环丝氨酸(DCS)是DdlA的抑制剂，可抑制菌株的生长。 ⑦HspX蛋白。研究发现，在宿主巨噬细胞中，低氧水平会诱导分枝杆菌细胞壁中的HspX高度表达，表明它在TB感染的潜伏期中起着重要作用。由于治疗期间人体容易产生抗生素耐药性，因此通过接种疫苗进行早期预防是控制感染的有效途径之一。卡介苗(Bacillus calmette-guerin，BCG)是目前可用的唯一结核病疫苗。有学者通过编码融合HspX-PPE44-EsxV抗原，得到了一种新型DNA疫苗，并在BALB/c小鼠感染模型中测试，结果表明，HspX融合疫苗可以在小鼠体内诱导高水平的特定细胞因子，而且在BCG增强免疫方案中使用该DNA疫苗可产生大量的IFN-γ、IL-12和TGF-β等细胞因子，从而取得更好的疗效。与DNA/RNA 合成有关的药物靶点 ①DNA回旋酶。DNA回旋酶由两个亚蛋白单元A（GyrA）和 B（GyrB）以异源四聚体的形式存在，DNA回旋酶在人体内不存在，但却是细菌生存的必需物质，抑制其作用可导致细菌死亡。氧氟沙星、左氧氟沙星和莫西沙星等喹诺酮类抗结核药物主要作用于结核分枝杆菌GyrA蛋白，阻止DNA 的复制和转录，从而杀死MTB。近年来，由于GyrA亚基易发生氟喹诺酮类耐药突变，药物研究及靶点筛选已转向GyrB亚基，相继出现了一些以GyrB 为靶点的药物，如苯并咪唑、尿素酶等。 ②RNA 聚合酶。RNA聚合酶在Mtb和真核生物中的结构存在一定差别。抗生素利福平(RIF)对快速增殖期和间断繁殖的Mtb 杀菌力都很强，与链霉素和异烟肼联用时可使它们的治疗效果增强RIF耐药性的产生主要是由 RNA 聚合酶 β 亚基的 rpoB 基因突变所致。 ③次黄嘌呤鸟嘌呤磷酸核糖转移酶。次黄嘌呤鸟嘌呤磷酸核糖转移酶（HGPRT）是一种细胞质酶，在体内广泛存在，它不仅参与嘌呤碱基的补救合成途径，对 DNA/RNA 的合成起重要作用，而且关系到嘌呤类药物的代谢，是调控该类药物药理效应和毒性反应的关键酶，两种吡咯烷核苷磷酸盐是目前针对Mtb-HGPRT最有效的抑制剂。 ④胸苷酸激酶。胸苷酸激酶(TMK)是一种核苷单磷酸激酶，在嘧啶合成中起关键作用，对细菌的DNA合成至关重要。TMK可催化ATP和脱氧胸苷-5'-单磷酸(dTMP)之间的可逆磷酸化，产生ADP和脱氧胸苷-5'-二磷酸(dTDP)，并通过再次磷酸化得到胸苷5'-三磷酸(dTTP)。Mtb-TMK在人体中的低同源性使其成为潜在的药物靶点。通过高通量筛选和核磁共振的方法，发现了两类新型 TMK抑制剂，分别是氰基吡啶酮类和萘啶类。以往的TMK 抑制剂都是胸苷单磷酸类似物或者是含有胸苷单磷酸结构，而这两类化合物是非胸腺嘧啶核苷类 TMK抑制剂，对TMK具有较好的选择性。与能量代谢有关的药物靶点在近年的研究中，针对结核分枝杆菌能量代谢系统，特别是氧化磷酸化途径的靶标研究已成为研究者关注的热点。虽然病原菌的有氧呼吸与真核生物类似，都依赖于一系列蛋白质复合体，包括NADH、琥珀酸、细胞色素c氧化还原酶和ATP合成酶，但是其结构和组装形式与真核线粒体和革兰氏阳性/阴性细菌均存在显著差异，其独特的特点使相关复合物成为理想的药物靶点。 ①ATP合成酶。Mtb中的ATP合酶是一种含有多个亚基的跨膜蛋白复合物，参与几乎所有活细胞的能量代谢和部分细胞间的信号传递。由atpE基因编码的ATP合酶C亚基是抑制剂贝达喹啉的主要作用靶点。但基因突变导致的贝达喹啉耐受加上贝达喹啉所导致的心律失常及恶心、头痛一系列副作用，限制了其临床应用。对一系列双喹啉衍生物评估发现，贝达喹啉SAR衍生的TBAJ-587和TBAJ-876化合物在体外和小鼠结核病模型研究中均显示出其对TB的潜在疗效，目前两类化合物皆处于临床研究的第一阶段。 ②细胞色素bc1: aa3。Mtb的细胞色素bc1: aa3是由甲萘醌、细胞色素c、还原酶(bc1)和细胞色素aa3型氧化酶组成的复合体，主要在呼吸链中发挥电子传递效能，显著影响ATP的合成。咪唑并[1, 2-α]吡啶类化合物Q203是针对细胞色素bc1: aa3复合体中细胞色素b亚基 (the cytochrome b subunit， QcrB)而研发的抑制剂，目前处于临床研究的第二阶段。 ③莽草酸激酶。莽草酸途径的终产物是分支酸盐，是一种芳香族氨基酸和甲基萘醌等物质的前体。在该途径中起关键作用的是莽草酸激酶 (shikimate kinase，SK)，该途径只存在于细菌、真菌、藻类和植物中，人体内不存在该途径，所以此途径中的关键酶可以作为抗结核靶点。目前对SK 的研究大多数停留在通过计算机辅助药物设计，对天然底物进行结构改造指导合成底物类似物阶段，但合成的化合物与SK 的亲和力往往较好，也预示了SK作为抗结核药物靶点的广阔前景。 ④细胞色素P450酶系。细胞色素P450 (cytochromeP450， CYPs) 是一类具有混合功能的氧化还原酶，在细胞合成与分解代谢活动中发挥关键作用。许多细菌P450 酶系的酶不超过5种，大肠杆菌中甚至没有P450 酶系，而在MTB中P450 酶系却含有20 多种酶，表明其在MTB代谢中发挥着重要的作用，也表明其中的一些酶很有可能成为新的抗结核药物靶点。近年来，对MTB中P450 酶系CYP51、CYP121和CYP141的研究较多。氯法齐明(Cfz)被视作核心二线药物，体外鉴定结果显示其可有效抑制CYPs。近年来，随着科学技术的进步和研究水平的提高，结核杆菌在分子水平上的生理功能得以精确阐释，多个药物和候选化合物的靶向作用机制得到了详细的阐明，相关的结合位点及其结合方式为新型抗结核小分子的开发提供了非常有价值的信息。相信不久的将来，对于这些靶点的新药开发一定会取得重要突破。参考资料 [1]吴疆,崔嘉伟,薛云新,王岱.抗结核药物靶点的研究进展[J].中国抗生素杂志,2022,47(11):1119-1127.DOI:10.13461/j.cnki.cja.007423. [2]王霞,朱宁屿,姜威,司书毅.抗结核药物靶点的研究进展[J].中国医药生物技术,2018,13(03):259-264. [3]陈晓博,李俊.抗结核药物靶点的结构研究进展[J].自然杂志,2021,43(05):335-342. 作者简介：小泥沙，食品科技工作者，食品科学硕士，现就职于国内某大型药物研发公司，从事营养食品的开发与研究。智药研习社近期课程报名来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPHI制药在线▼点击阅读原文，进入智药研习社~

上市批准

2023-03-24

·佰傲谷BioValley

甲贝视野 | 越了解，越无畏，这一份结核病手册请查收

导语2023年3月24日是第28个世界防治结核病日。世界卫生组织（WHO）发布的主题为：“是的！我们可以终止结核病（YES! WE CAN END TB）！”，旨在呼吁各国广泛参与，共同终结结核病的流行。我国疾病预防控制局最新发布的宣传主题“你我共同努力，终止结核流行”。正文感染结核病的人大多脸色苍白，身形消瘦，咳嗽严重，故西方称之为“白色瘟疫”。历史上三国著名军事家诸葛亮就是脊椎结核，所以年纪轻轻就是扶杖而行，最后死于吐血。红楼梦中的女主角林黛玉是肺结核，最后吐血而亡。波兰著名作曲家肖邦，俄国批判现实主义作家契诃夫，德国著名文学家席勒，美国诗人梭罗，以及英国诗人雪莱——他曾向世人呼喊“冬天来了，春天还会远吗”，自己却未能看到人类战胜肺结核的春天。中国近代文学大家鲁迅先生，也是身患肺结核最后早逝。今天，我们一起来了解下什么是结核病，如何预防、诊断和治疗这种疾病，以及关于它的最新研究进展。1.结核病和结核杆菌结核杆菌(Mycobacterium Tuberculosis,MTB))是德国细菌学家Robert Koch于1882年3月24日发现的，它是引起人和动物结核病的病原菌。并将其分为人型、牛型、鸟型和鼠型4型，其中人型菌是人类结核病的主要病原体。图1.结核病常见临床表现肺结核(Tuberculosis，TB)就是主要由人型结核杆菌侵入肺脏后引起的一种具有强烈传染性的慢性消耗性疾病。常见临床表现为咳嗽、咯痰、咯血、胸痛、发热、乏力、食欲减退等局部及全身症状。肺结核90％以上是通过呼吸道传染的，病人通过咳嗽、打喷嚏、高声喧哗等将带菌液体喷出体外，健康人吸入后就会被感染。据WHO的《2022年全球结核病报告》显示：2021年全球约有1060万结核病患者，比2020年增加4.5%；有160万人死于结核病，我国2021年估算的结核病新发患者数为78.0万。受新冠肺炎疫情的影响，预计2020年和2021年结核病作为单一传染源的死亡原因将降至第2位。2.结核杆菌与宿主免疫系统MTB是一种非常成功的细胞内病原体，与宿主共同进化。宿主免疫细胞被触发成不杀灭MTB，导致MTB的潜伏感染，其通过形成肉芽肿在宿主和病原体之间保持平衡。患者体内的潜伏期肺结核的再激活率从5到10%。宿主细胞不能抑制MTB生长导致肉芽肿病变，坏死的巨噬细胞死亡和炎性细胞募集增。这种宿主免疫力的退避反映了致病性分枝杆菌在宿主细胞内存活、存留的高度进化和多因子能力。MTB开发的逃避宿主天然免疫的复杂机制包括细胞溶质逃逸，抗菌肽的限制性生成，吞噬体成熟的阻断，细胞凋亡，炎性体激活和自噬的调节。3.结核病的预防图2.如何预防结核病1.控制传染源。早期发现传染源和彻底治愈涂阳肺结核病人是控制传染源的关键。对确诊的结核病人，应及时转至结核病防治机构，进行统一管理，并实行全程督导短程化学治疗(DOTS)。2.切断传播途径。结核菌主要通过呼吸道传播，患者和家属应佩戴一次性外科口罩；开窗通风，保持空气新鲜，可有效降低结核病传播；餐具煮沸消毒或用消毒液浸泡毒，同桌共餐时使用公筷；衣物、寝具、书籍等污染物可在烈日下暴晒进行杀菌。3.保护易感人群。进行卡介苗(BCG)接种：可使未受过结核菌感染者获得对结核病的特异免疫力；化学药物预防：对于高危人群，可以遵医嘱预防服用抗结核的化学药物；生活有规律：避免长期过劳和精神紧张，戒烟、饮食均衡，适当进行锻炼，增强抵抗力。4. 结核病的诊断及治疗1.体外诊断IVD世界卫生组织(WHO)推荐使用快速分子检测技术作为结核病的初始诊断方法，分子检测技术准确可靠，在早期发现结核病和耐药结核病方面发挥着重要作用，是终止结核病流行（END TB）策略中加强结核病实验室工作的重要内容。2021年，WHO推荐分子诊断技术的原则由特定技术类型推荐改为基于类别进行推荐，依据操作复杂程度和自动化水平对诊断技术进行分类，共批准6项用于结核病诊断和抗结核药物耐药性检测的分子诊断技术：l 低复杂程度自动化检测平台：赛沛Xpert MTB/XDRl 中等复杂程度自动化检测平台：雅培Abbott RealTime MTB &MTB RIF/INH、碧迪BD Max MDR-TB、罗氏cobas MTB & MTB-RIF/INH、海恩/布鲁克FluroType MTB & MTBDRl 高复杂程度尼：普洛Genoscholar PZA-TB检测 2.化学药物治疗临床上针对敏感结核分歧杆菌广泛采用的标准治疗方案由利福平、异烟肼、吡嗪酰胺和乙胺丁醇组成，其机理为杀菌和抑菌作用，具有较好的治疗效果。但目前，耐多药和广泛耐药结核分枝杆菌感染在世界范围内广泛流行。针对这一现象，WHO推荐用药不断推陈出新，从以往的注射药物治疗转为短程口服治疗，以缩短药物疗程，防止细菌耐药。此外，结核新药研发也取得很大的进展。抗结核新药(贝达喹啉、普瑞玛尼、德拉马尼等)已进入临床使用，对于耐药结核治疗及缩短疗程具有良好的效果。包括 TBA-7371、 GSK-656、 OPC-167832、Telacebec、Delpazolid、Sutezolid、SQ-109等候选药物已经进入Ⅱ期临床试验。3.免疫治疗耐药结核病的治疗，除了开发新型抗结核药物外，提高宿主免疫应答水平和减轻宿主免疫炎性损伤的免疫治疗逐渐受到重视。● 细胞因子治疗通过注射或者雾化吸入的方式提高宿主体内特定细胞因子的含量，对宿主进行免疫干预来激发宿主的抗结核免疫应答。例如γ－干扰素、粒细胞－巨噬细胞集落刺激因子、、白细胞介素１/2等。● 免疫细胞治疗通过体内激活自体免疫效应细胞，或体外扩增自体或异体免疫效应细胞，然后回输给患者纠正免疫失衡和改善免疫功能，提高宿主抗感染应答水平。例如Ｖγ２Ｖδ２Ｔ细胞、固有自然杀伤Ｔ细胞等。4.治疗性疫苗实验性疫苗ID93+GLA-SE是由西雅图的Christopher B. Fox博士和Access to Advanced Health Institute（前身为传染病研究所）的科学家开发的。它是一种重组亚单位疫苗，由结核分枝杆菌的4种蛋白质与GLA-SE（一种免疫刺激佐剂）结合而成。这种冻干配方不需要冷藏，在注射前与无菌水混合。对于偏远地区来说，不需要冷链运输的高效疫苗将成为结束这一流行病的重要工具。5. 最新研究进展自新型冠状病毒全球大流行以来，结核分枝杆菌已成为仅次于SARS-CoV-2的第二大单一感染致死病原，同时感染结核分枝杆菌和艾滋病病毒的患者更是高危人群。近期，北京协和医院医院李永哲教授、石家庄市第五医院戴二黑教授团队发表于《感染杂志》（Journal of Infection）一项横断面研究，对成年结核病患者新冠灭活疫苗加强针的安全性和免疫原性进行分析。临床数据表明：尽管灭活疫苗加强针提高了结核病患者的SARS-CoV-2特异性抗体水平和中和活性，但结核病患者的体液免疫差于健康人群，可进行动态血清抗体监测以推断接种加强针的最佳时机，从而发挥疫苗的最大优势。同时，相对于第2剂灭活疫苗，加强接种可实现结核病患者广泛的体液免疫，尽管仍低于健康人群。而相对于野生毒株，Omicron BA.4/5的中和活性仍然较低，虽然两组人群均已接种第3剂COVID-19疫苗。Omicron亚变种的刺突蛋白RBD突变使其获得了突破性感染，并且能够逃避由COVID-19疫苗构建的免疫保护。因此，为Omicron变异株定制疫苗必不可少。让我们一起努力，对抗结核，守护健康!❒ 第七届宁波生物产业论坛暨BioDeveloper药研者大会大会名称丨第七届宁波生物产业论坛暨BioDeveloper药研者大会大会主题丨潮起甬南 · 破浪笃行大会时间丨2023年4月26-27日大会地点 | 浙江 · 宁海（喜来登酒店-桃源街道天明中路108号）大会规模 | 200+主办单位 | 中共宁海县委组织部、宁海县生物产业园管理中心承办单位 | 甲贝医药支持单位 | 中国生物工程学会、宁波市经信局、宁波市科技局、宁波市投资促进署、中共宁海县委统战部、宁波市医药行业协会、宁波体外诊断联盟、宁波股权交易中心、“科创中国”生物医药产业科技服务团、美国华人生物医药科技协会(CBA)媒体支持 | 佰傲谷BioValley、动脉网扫码报名（免费参会需审核）▽邀请辞本届论坛将以“潮起甬南，破浪笃行”为主题，汇聚政产学研等各路行业领袖专家。于暮春日，游宁海，凭栏远眺，闲谈些许求药故事。第七届宁波生物产业论坛暨BioDeveloper药研者大会将于4月26日-27日在浙江宁海举办。我们期待药物研发者们暂时放下严肃的“奋斗者”姿态，换一种风格、换一种情绪，在严谨的工作之余，重新认识一下并肩作战的朋友们，好好的交流一下当前与未来？风景几许？岂不美哉？推荐阅读：最新议程发布 | 第七届宁波生物产业论坛4月宁海召开！点击“阅读原文”，立即报名~

临床研究

2008-10-29

·BioSpace

Sequella, Inc. Presents Data on Synergy Between Investigational New TB Drugs SQ109 and TMC207

Study results to be presented at 2008 ICAAC/IDSA Joint Meeting ROCKVILLE, Md., Oct. 28 /PRNewswire/ -- Sequella, Inc., a clinical-stage biopharmaceutical company focused on commercializing products to treat infectious diseases of epidemic potential, announces the successful demonstration of synergistic activities and improvement of minimal inhibitory concentration (MIC) resulting from in vitro combination studies of Sequella lead TB drug candidate, SQ109, and Tibotec's lead TB drug candidate, TMC207. Both drug candidates are currently undergoing human clinical studies. Results from these studies were presented on October 28th at the Interscience Conference on Anti-Microbial Agents and Chemotherapeutics (ICAAC) and Infectious Disease Society of America (IDSA) joint meeting in Washington, DC. The collaboration between Sequella and Tibotec was designed to investigate in vitro interactions of SQ109 for synergistic, additive, or antagonistic activity in the presence of TMC207, using a number of clinical and laboratory strains of both drug sensitive and drug resistant M. tuberculosis (MTB). In vitro interactions investigated included synergy studies, rate of killing, post antibiotic effect and intracellular activity against MTB in macrophages. There were no antagonistic activities observed in any combination studies. SQ109 and TMC207 in combination were either synergistic or additive with the various MTB strains and showed increased rate of killing, enhanced post antibiotic effect and intracellular killing activity. Results showed that the SQ109 and TMC207 drug combination was extraordinary potent, with greater than 90% kill of MTB as early as 1 day after drug combination exposure. Dr. Carol Nacy, CEO of Sequella said, "We are very pleased to be collaborating with Tibotec, a world renowned product development organization, and we look forward to our continuing partnership to examine these important drug synergies in animal models of TB." The next step of the collaboration will be to complete a series of in vivo studies in animal models of TB, currently underway. About SQ109 The company's lead drug candidate, SQ109, completing Phase I clinical trials, is a new diamine antibiotic that could replace one or more of the current first-line anti-tuberculosis drugs to simplify or shorten therapy. SQ109 was granted U.S. FDA Fast Track and FDA/EMEA Orphan Drug Designation in 2007. About Sequella Sequella is a clinical stage biopharmaceutical company focused on commercializing improved treatments for infectious diseases of epidemic potential. The company leverages its global influence, R&D platforms and infectious disease expertise to proactively address emerging health threats. Through focused execution, clear commercialization pathways, and strategic partnerships, Sequella intends to commercialize a broad product portfolio designed to treat global health threats with significant market opportunity. Forward-Looking Statement This press release contains forward-looking statements that are subject to risks and uncertainties, and includes statements that are not historical facts. Actual results could differ significantly from results discussed. Sequella disclaims any intent or obligation to update forward-looking statements, except as required by law. CONTACT: Alicia Moran, +1-410-991-7027, for Sequella, Inc. Web site:

合作小分子药物抗体孤儿药快速通道

100 项与 SQ-109 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	SQ-109	-	DB05186

研发状态

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适应症	最高研发状态	国家/地区	公司	日期
肺结核	临床3期	俄罗斯	Infectex LLC	2022-08-29
幽门螺杆菌感染	临床2期	-	Sequella, Inc.	2012-03-01
结核	药物发现	美国	Sequella, Inc.	2006-09-01

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临床结果

适应症

分期

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT01785186 (CTgov)	临床2期	肺结核	365	pyridoxine+Ethambutol+Rifampicin+Isoniazid+Pyrazinamide (Arm 1 (R35))	窪構廠鑰蓋蓋簾窪鑰蓋(膚鏇遞鑰鏇餘鬱艱齋遞) = 餘鬱窪鬱觸襯網憲獵壓齋齋憲範製選夢鏇顧襯 (膚廠積憲衊襯鹹衊鏇築, 鏇鑰衊襯範醖鑰鑰醖艱 ~ 夢糧蓋壓積膚顧鬱鹽蓋) 更多	-	2017-09-20
				pyridoxine+SQ109+Rifampicin+Isoniazid+Pyrazinamide (HRZQ)	窪構廠鑰蓋蓋簾窪鑰蓋(膚鏇遞鑰鏇餘鬱艱齋遞) = 艱糧選憲夢製糧製艱艱齋齋憲範製選夢鏇顧襯 (膚廠積憲衊襯鹹衊鏇築, 遞鑰獵醖觸憲選繭鹹積 ~ 範繭觸顧觸鏇糧廠糧簾) 更多