Tuberculosis, Central Nervous System

BV100 Phase 2 preliminary results suggest BV100 is generally safe and well tolerated and showed strong initial signs of efficacy in VABP patientsStrategic investment from GIBF and launch of BV100 clinical program in ChinaSecond lead asset, alpibectir Phase 2a trial completed in April showing human proof of concept in tuberculosis BASEL, Switzerland, Oct. 16, 2024 (GLOBE NEWSWIRE) -- BioVersys AG, a multi-asset, clinical stage biopharmaceutical company focusing on research and development of novel antibacterial products for serious life-threatening infections caused by multi-drug resistant ("MDR") bacteria, announced today the completion of the last patient's last visit in the Phase 2 clinical trial with its lead asset BV100, the company's novel formulation of rifabutin suitable for intravenous administration. The Phase 2 multicenter, open label, randomized, active controlled study evaluated the pharmacokinetics, efficacy and safety of BV100 in adult patients with ventilator associated bacterial pneumonia (VABP) suspected or confirmed to be due to Carbapenem Resistant Acinetobacter baumannii (CRAB). Preliminary analysis of the data shows that the primary endpoint was met. BV100 is generally safe and well tolerated, met the expected pharmacokinetic targets and showed strong signs of efficacy in VABP patients with confirmed CRAB infection. In Part A of the study, the 14- and 28-day all-cause mortality (ACM) for BV100 was 12.5% and 25% respectively compared to the best available therapy control arm with 40% and 60% ACM respectively in patients with carbapenem resistant Acinetobacter infections. Similar trends in the test of cure and microbiological endpoints were seen. Full top line results from the trial are expected in early 2025 once analysis of the data has been finalized. BV100 is based on the newly identified mode of action for the active uptake of rifabutin into Acinetobacter baumannii-calcoaceticus complex and is being developed for hospital infections caused by Acinetobacter baumannii, including CRAB strains. There is a serious lack of effective and safe treatment options for CRAB infections and mortality rates in hospitals can be as high as 50%. CRAB has been designated a priority pathogen by the World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC). Due to the high unmet need and based on the current carbapenem resistance rates in Acinetobacter baumannii, we estimate in excess of 1 million hospital treated patients across the United States, Europe, the Middle East and China that could benefit from BV100. BioVersys is committed to advancing the clinical development of BV100 in a global Phase 3 registration trial, which it expects to initiate in the second half of 2025. To date, BV100 has been administered to over 230 subjects, at doses of up to 900 mg and over periods of up to 14 days in Phase 1 and 2 clinical trials and was considered generally safe and well tolerated. The strong clinical data package comprising the first in human studies, the Phase 2 in VABP patients, two drug-drug interaction studies, studies in renally and hepatic impaired patients and a bronchoalveolar study provides the foundation for progressing BV100 into the final clinical Phase. Dr. Glenn E. Dale, Chief Development Officer of BioVersys: "We are making great progress with our clinical evaluation of BV100, and we are very pleased to have met this latest milestone with the final visit of our last patient in the Phase 2 trial, with BV100 demonstrating strong signs of efficacy. We are now looking forward to finalizing the data ahead of our planned readout early next year, which we expect will build on the promising safety profile that BV100 demonstrated in Phase 1 and provide a further basis for our planned Phase 3 study." Prof. David Paterson: "BV100 could bring a much-needed solution for patients with an unmet need due to carbapenem resistant infections caused by Acinetobacter. Its safety profile and ease of use in an ICU setting, together with the strong signs of efficacy seen in the Phase 2 trial, make BV100 a compelling treatment option to be tested in a pivotal Phase 3 trial of VABP patients with confirmed CRAB infection.” In addition to the progress of BV100, the company's second clinical asset, alpibectir a first in class molecule for tuberculosis which is developed in partnership with GSK, completed a Phase 2a clinical trial earlier this year. Alpibectir delivered a proof of concept in patients and was also shown to be generally safe and well tolerated. Alpibectir will continue to be developed in close partnership with GSK. In May 2024, BioVersys announced the expansion of the strategic collaboration with GSK and the extension of the Series C round by CHF 14.7 million. This was complemented by the strategic investment of the investment firm Guangzhou Sino-Israel Bio-Industry Investment Fund 2 LLP (GIBF) of US$ 6 mio (approximately CHF 5.17 mio) announced in September 2024. This investment provides a strategic partnership to extend our development of BV100 to China as well as adding additional flexibility to our cash position. BV100 Phase 1 study in China is expected to start in 1H 2025 as part of our preparation for a global Phase 3 registration study. Dr. Marc Gitzinger, Chief Executive Officer and founder of BioVersys: "BioVersys has made significant progress during 2024 on multiple fronts. Our lead asset BV100 holds a lot of promise towards treating patients with very severe, drug-resistant bacterial infections, with limited or no treatment options. We are now looking forward to engaging with regulatory authorities to expedite the Phase 3 development of our lead asset in order to make this drug available as soon as possible to patients in need. Besides our clinical assets, BV100 and alpibectir, we are also very happy with the progress our pre-clinical pipeline in the form of BV200 and BV500, which is also moving forward. On the business side, we have extended our collaboration with GSK and we recently announced the investment from GIBF that will enable us to extend our clinical development to China. We remain committed to bringing new treatment options for drug resistant infections to patients in dire need and take great encouragement from the headway we are making towards that goal." About BV100BV100 is a novel formulation of rifabutin suitable for intravenous administration, with a recently discovered novel mode of action showing an active uptake of rifabutin into the Gram-negative bacterial species, Acinetobacter baumannii. For the first time, the lead candidate allows for the targeting of the RNA-polymerase enzyme in Gram-negative bacteria with a human-suitable dose. BV100 is being developed for the treatment of infections caused by Acinetobacter baumannii calcoaceticus complex (ABC), including Carbapenem-Resistant ABC (CRAB) in critically important indications of ventilator associated bacterial pneumonia (VABP), hospital-acquired bacterial pneumonia (HABP) and bloodstream infections (BSI). BV100 was granted QIDP Designation by the U.S. FDA in May 2019 for use in the treatment of VABP, HABP and BSI, making BV100 eligible for priority FDA review, Fast Track designation, and a five-year extension of market exclusivity upon approval of the first QIDP indication. About Acinetobacter baumanniiAcinetobacter baumannii calcoaceticus complex (ABC) are Gram-negative bacteria found in the environment (e.g., in soil and water) and an opportunistic pathogen in humans, typically infecting critically ill and immunocompromised patients, that can result in severe pneumonia and bloodstream infections in addition to affecting other parts of the body. ABC is considered a significant worldwide threat in the healthcare setting given its ability to survive for prolonged periods on surfaces, combined with its ability to develop or acquire resistance to standard of care antibiotics, e.g. carbapenems. Carbapenem-resistance as well as multidrug-resistance (MDR) rates for ABC are among the highest recorded for any bacteria in current times (The Lancet 2022; 399: 629–55). Incidence and resistance rates for ABC are trending upwards and COVID-19 has exacerbated this significantly. BioVersys forecasts the annual number of carbapenem-resistant A. baumannii infections in hospitals to have surpassed one million globally and due to the limited treatment options, such infections come with high (up to 50%) mortality rates. About alpibectirAlpibectir is a first in class small molecule acting on a transcriptional regulator protein in Mycobacterium tuberculosis (TB). Alpibectir rejuvenates the existing drug ethionamide (Eto), by both potentiating the activity of Eto and restoring the antibacterial activity of Eto towards Eto-resistant TB. The resulting fast bactericidal effect of alpibectir/Eto at low and safe doses offers the potential to replace Isoniazid (INH) in future TB drug regimens for MDR/XDR-TB but also in TB-meningitis patients or INH-mono-resistant patients. Alpibectir is being co-developed with our long-term partner GSK and the molecule originates form a very successful public-private partnership with the Pasteur Institute Lille and the University of Lille. The program was supported by several grants from the Wellcome Trust, EU IMI joint undertaking and EDCTP. Alpibectir in combination with Eto has the orphan drug designation (ODD) and QIDP designation from the US FDA. About tuberculosis (TB) Tuberculosis (TB) is one of the leading causes of death worldwide. Its causative agent is the bacterial pathogen Mycobacterium tuberculosis (Mtb). Worldwide, an estimated 10.6 million people developed TB in 2022 and an estimated 1.30 million died from TB. The WHO estimates that there were 410’000 new cases with resistance to rifampicin – the most effective first-line drug – most of them were multi-drug resistant (MDR). MDR-TB remains a public health crisis and a health security threat. Worldwide, only 63% of MDR-TB patients are currently successfully treated.1 In the modern world of global travel, and ease with which infections spread, it is very worrying to note that two-thirds of the global total of TB cases was in eight countries: India (27%), Indonesia (10%), China (7.1%), the Philippines (7.0%), Pakistan (5.7%), Nigeria (4.5%), Bangladesh (3.6%) and the Democratic Republic of the Congo (3.0%). Furthermore, 3.3% of all new and 17% of reoccurring TB cases were MDR/RR-TB. About BioVersysBioVersys AG is a multi-asset, clinical stage biopharmaceutical company focused on identifying, developing and commercializing novel antibacterial products for serious life-threatening infections caused by multi-drug resistant (“MDR”) bacteria. Derived from the company’s two internal technology platforms (TRIC and Ansamycin Chemistry), candidates are designed and developed to overcome resistance mechanisms, block virulence production and directly affect the pathogenesis of harmful bacteria towards the identification of new treatment options in the antimicrobial and microbiome fields. This enables BioVersys to address the high unmet medical need for new treatments against life-threatening resistant bacterial infections and bacteria-exacerbated chronic inflammatory microbiome disorders. The company’s most advanced research and development programs address nosocomial infections of Acinetobacter baumannii (BV100, Phase 2), and tuberculosis (alpibectir, Phase 2a, in collaboration with GlaxoSmithKline (GSK) and a consortium of the University of Lille, France). BioVersys is located in the biotech hub of Basel, Switzerland. BioVersys contact Sylvia Mundt, Tel. +41 61 633 22 50; Mail: IR@bioversys.com www.bioversys.com https://twitter.com/Bioversyshttps://www.linkedin.com/company/bioversys-ag 1 Global Tuberculosis Report 2023 WHO

IND2025主会场授课已被预定，大会第一天下午茶歇前授课时间段预定开始，咨询热线：177 0186 0390。点击图片，查看IND2024会后报告 文章来源：柯瑞斯·IVD 摘  要  结核病作为世界上最致命的传染病之一,是全球性危害公众健康的公共卫生问题。我国是结核病高负担国家,发病人数仅次于印度,结核病防控形势依然严峻,所以早期迅速、准确诊断是防治结核病的关键。近年来,为更好控制、诊断结核病,国内外已开展多项研究并取得了一定的创新结果。因此,本研究将从细菌学、免疫学、分子生物学的相关检测及结核病组学研究等方面总结结核病实验室诊断的现状与进展,并作如下综述。 结核病(tuberculosis，TB)是一种传染性疾病，由结核分枝杆菌（MTB）引起，多通过空气进行传播，常见症状为咳嗽、发热、盗汗、体重减轻等。结核病感染人数约占全球的1/4，每天约4 000人死于该病，近30 000人感染可预防、治愈的结核病[1]。据世界卫生组织（WHO）统计2021年约有1 060万人患结核病，患病人数与2020年相比增加4.5%，其中160万人死于结核病[包括18.7万人类免疫性缺陷病毒（简称HIV）阳性者][2]。结核病实验室诊断是发现传染源的主要方法，但传统检测方法周期长、灵敏度低，无法满足临床需求。因此联合运用新的辅助诊断方法，对全球结核病研究和防控具有重要意义。本研究将从细菌学、免疫学、分子生物学的相关检测及结核病组学研究等方面总结结核病实验室诊断的现状与进展，并作如下综述。 1 结核病细菌学检测 目前，结核病的细菌学检测仍是诊断感染结核病的金标准。痰涂片和培养是应用最广泛的结核病实验室诊断技术, 常见方法为抗酸涂片染色法、荧光染色法、传统结核菌固体培养和全自动结核分枝杆菌培养仪快速检测。 1.1 涂片染色与荧光染色技术  萋尼氏抗酸染色痰涂片显微镜检查是最经典的结核分枝杆菌检测方法，具有经济、迅速、操作简单的优点，但灵敏度较低。有研究对抗酸染色阳性病例进行分析，在收集的结核抗酸染色14 060例样本中，阳性307例，阳性率为2.18%[3]。可见此方法出现假阴性的情况较多，受主观因素和标本质量影响较大。荧光染色则运用荧光提高显微镜检查的灵敏度，但由于价格昂贵目前难以普及。 1.2 培养技术  传统固态培养法灵敏度略高于涂片法，是鉴定活菌的可靠方法，还可进一步进行菌种鉴定和药敏试验；但其培养时间长，需4~6周才能检测到菌种，且无法区分结核分枝杆菌与非结核分枝杆菌。培养仪的原理是基于液体培养法，以全自动分枝杆菌培养监测仪为（BD公司，型号：BACTEC MGIT960）代表，其通过测定液体培养基中氧气消耗量来判定 MTB有无生长。王巍等[4]比较了罗氏培养法与BACTEC MGIT960检测系统在肺结核中的应用，结果显示BACTEC MGIT960培养阳性率为67.6%，罗氏培养阳性率为53.3%，且前者检测周期明显缩短。但也存在该技术对实验室生物安全级别要求高、成本高等缺点，不能大规模普及。因此，应联合其他辅助诊断方法提高阳性检出率，在此基础上寻找细菌学证据。 2 结核病免疫学检测 免疫学检测方法包括TB抗原和抗体检测、多种抗体联合检测、结核菌素皮肤试验（tuberculin skin test，TST）、γ-干扰素释放试验（interferon-γ release assays，IGRAs）、重组结核杆菌融合蛋白（ESAT6-CFP10，EC）皮肤试验等。  2.1 结核病抗原和抗体检测技术  TB 抗原包括菌体细胞、结核菌素（PPD）、脂阿拉伯甘露聚糖（LAM)、热休克蛋白65（HSP）抗原、早期分泌性抗原靶-6（ESAT-6) 等。由于抗原成分复杂且存在交叉抗原，所以，目前通过技术对抗原进行表达和纯化，大量制备TB蛋白质成分以检测人体内是否存在抗体。胶体金免疫层析法检测结核病患者中特异性结核抗体免疫球蛋白（Ig）G／IgM 的灵敏度为41.15%、特异度为91.67%[5]，可见多种抗原和抗体联合检测有助于提高检测的敏感性，但仍受患者年龄、检测的抗体类型(IgG、IgM、 IgA) 、结核病感染类型等多方面因素的影响。 2.2 结核菌素皮肤试验技术  TST是实验室诊断方法之一，是基于Ⅳ型变态反应原理建立的皮肤试验，具有快速、简单、低成本的优点，但特异性较低，曾接种卡介苗(BCG)或接触非结核分枝杆菌的环境均可导致TST假阳性。 2.3 γ-干扰素释放试验技术  IGRAs原理为机体初次感染结核分枝杆菌后致敏T淋巴细胞，再次感染时γ-干扰素在内的细胞因子释放，通过检测γ-干扰素判断感染状况。刘珍敏等[6]对299名儿童研究对象进行结核感染T细胞斑点试验（T-SPOT.TB）、涂片检查，与TST比较灵敏度和特异度，结果显示T-SPOT.TB灵敏度远高于TST，且标本获取方便，能快速诊断。 虽然IGRAs具有较好的诊断价值，但测试费用昂贵，对实验室设备要求较高，给结核病高负担国家带来较大压力。WHO在2022年发表的报告中指出[7]：基于特定抗原的新结核杆菌抗原皮肤试验(TBSTs)已经开始被研究，这些试验结合更简单的皮肤试验和高特异性的IGRAs，将可能成为结核感染诊断的有效工具。 2.4 EC皮肤试验技术  2021年的一项研究显示：EC皮肤试验与T-SPOT.TB试验相比，EC皮肤试验显示出较高的特异性和灵敏度，具有良好的安全性和较高的诊断准确性[8]。此外，EC皮肤试验在HIV感染者诊断中也显示出价值，无论是否接种卡介苗，EC皮肤试验对HIV感染者均有较高的诊断价值。因此，EC皮肤试验可能是一种有效的替代诊断试验，用于HIV流行率高和卡介苗接种高的环境或人群，但尚未得到系统的审查，因此还需进一步研究。 3 结核病分子生物学检测 早诊断、早隔离、早治疗能够减少肺结核发病和死亡，但MTB生长缓慢，通过传统实验室检查难以快速确诊，而分子生物学诊断可更快地进行病原检测。目前，应用分子生物学诊断结核病的方法主要包括聚合酶链式反应（PCR）技术、环介导等温扩增（LAMP）技术、线性探针分析 (LPA)技术、基因芯片技术、基因组测序技术、基质辅助激光解吸电离飞行时间质谱（MALDI-TOF MS）技术等。 3.1 聚合酶链式反应技术  PCR通过在体外模拟体内DNA复制的过程获得大量DNA，包括变性、退火、延伸三个阶段。PCR是传统的分子生物学检测方法，成本低、方法成熟、有较好的检出率，但存在易污染、非特异性扩增、会导致假阳性等缺点。因此产生了很多改进的方法，例如即时检验（point of care testing，POCT）技术、荧光定量（real-time）PCR技术、数字PCR (digital PCR，d PCR)技术。 3.1.1即时检验技术  POCT是一种集核酸提取、检测、扩增为一体的新型结核分子诊断技术，无需在特定的分子实验室操作，该技术主要用于门诊及住院的疑似结核病患者初筛及鉴别诊断中，可在2 h内从痰液等样本中检测是否存在结核分枝杆菌复合群，能够极大提高结核病病原学阳性率，更好地服务于临床并提高诊疗水平。于佳佳等[9]首次成功建立并验证了针对MTB的PCR-CRISPR检测技术具有敏感度与特异度高、稳定性好、成本低等特点。基于CRISPR/Cas的超敏诊断技术为TB诊断提供了可能，且可能适合于POCT。 3.1.2 荧光定量PCR技术  Gene Xpert MTB/RIF检测是基于实时荧光定量PCR原理的一种检测技术，可在2 h内检测样本中是否存在结核分枝杆菌及是否耐药，是目前最快的结核病分子诊断技术之一，可以准确地排除非结核分枝杆菌，并分离鉴定出RIF抗性。该方法操作简便、检测准确性高、污染概率小，但价格昂贵、培养阴性菌量少且对HIV患者的灵敏度不够。为弥补这些不足，Gene Xpert MTB/RIF Ultra（简称Xpert Ultra）增加了两种MTB检测分子靶标(IS1081 和IS6110)以提高检测灵敏度，并且有更低的TB检测限（LOD），与Gene Xpert MTB/RIF特异性相当[10]。因此Ultra可显著提高结核病的检测率，尤其是对于低细菌性患者。对于肺外结核的诊断，一项研究显示Xpert Ultra对76例行CSF培养的结核性脑膜炎患者检测敏感度明显高于MGIT 960培养[11]。此外，Xpert Ultra在HIV阳性患者中表现出高灵敏度。Xpert Ultra 在标本含菌量少、肺外结核和艾滋病合并结核患者中的灵敏度较好。自2021年来，WHO建议将粪便与痰一起作为一种标本类型用于Xpert Ultra检测结核病的初始测定，可在紧急情况时作为首选方法[12]。对于儿童来讲，痰液难以获得，可选择粪便代替检测，但该技术特异性较低，且成本较高，还需进一步研究。 3.1.3 数字 PCR技术  dPCR是一种比荧光定量PCR具有更高灵敏度和绝对定量的微量DNA鉴定技术，是基于单分子PCR方法进行计数的核酸定量，绝对定量不受标准曲线影响，具有高灵敏度、低样本需求量低、高耐受性等特点。研究显示可使用d PCR来调查MTB的异耐受性，通过对katG和rpoB基因进行荧光定量PCR突变检测，确定结核分枝杆菌的异质性耐药率，这两种基因通常分别与异烟肼和利福平耐药有关[13]。微滴数字PCR（droplet digital PCR, ddPCR）能够检测出突变株和野生型菌株，这使其成为早期诊断和管理耐药结核病的宝贵工具，同时也印证早期发现和管理耐药结核病对于控制结核病进展的重要性。数字PCR技术还未能获得大量临床研究，这也有可能是与其仪器设备和试剂昂贵有关，还需进一步研究。 3.2 环介导等温扩增技术  LAMP技术是一种新的核酸扩增方法，具有简单、快速、操作简便的特点。该技术在灵敏度、特异性和检测范围等指标上优于PCR技术。其不依赖热循环设备而实现高通量快速检测，检测成本远低于荧光定量PCR。但因其灵敏度高，开盖容易形成气溶胶污染，易造成假阳性。有研究将LAMP技术与传统方法（涂片镜检和MGIT 960）相比，结果显示TB-LAMP检测MTB的效能更高,且涂片镜检和TB-LAMP并联合检测肺泡灌洗液的敏感性更好[14]，这提示LAMP技术可作为诊断儿童肺结核的替代试验。对于结核性脑膜炎的诊断，LAMP技术阳性率高、耗时短，能早期获得结果[15]，表明LAMP技术对于早期诊断结核性脑膜炎具有较好的参考意义。 3.3 线性探针分析技术  LPA技术是通过应用生物素标记引物进行DNA的扩增，将扩增产物变性后与固定在尼龙膜上的特异寡核苷酸探针进行杂交，通过酶联免疫显色法显示结果，其是耐多药结核病检测方法之一。该方法具有较高的灵敏度和特异度，且检测速度快。利用该技术的仪器比较有代表性的为INNO-LiPA Rif.TB和MTBDRplus。2008年WHO批准使用一线探针法基因型MTBDRplus v1.0，用于快速检测耐多药结核病(MDR-TB)；2011年，新版本的LPA技术出现基因型MTBDRplus v2.0 [16]。二线结核病药物耐药性基因（基因型MTBDRsL v2.0）2015年出现，用于检测与氟喹诺酮(FQs)和二线注射药物(SLDIs)耐药性相关的突变，Singh等[17]研究表明基因型MTBDRsL v2.0检测FQ和SLIDs的特异性分别为92.31%和100.00%，灵敏度为100.00%。MTBDRsL是目前可检测广泛耐药结核的分子诊断技术，但是该方法的成本较高，仍是耐多药结核病高负担国家的问题之一。 3.4 基因芯片技术  基因芯片又称DNA芯片，测序原理为杂交测序法，通过与一组已知序列的核酸探针杂交进行核酸序列测定，得出一组序列完全互补的探针序列，进而重组出靶核酸的序列。该方法将多种探针固定在支持物上，可一次性对样品大量序列进行检测和分析，具有自动化程度高、操作序列多、检测效率高的优点，可用于菌种的鉴定及耐药性检测。2018年，有研究证明生物芯片技术对RIF和INH耐药及耐多药结核病检测具有良好的敏感度和特异度，值得在我国临床推广[18]。其中生物芯片对RIF检测的敏感度为86.08%，特异度为97.7%；对INH耐药的敏感度为79.36%，特异度为98.71%，对MDR-TB检测的敏感度为78.01%，特异度为98.86%。此外，对于涂阳肺结核患者MTB菌种鉴定，基因芯片法对结核分枝杆菌复合群鉴定符合度为100.00%，可较好的鉴定结核分枝杆菌菌种，并与常规菌培养结果具有高度一致性[19]。相较于痰涂片、痰培养方法，基因芯片技术可提高阳性检出率，但是基因芯片仍然存在着许多难以解决的问题，例如技术成本昂贵、复杂、重复性差、分析泛围较狭窄等，还需进一步研究。 3.5 基因组测序技术  基因测序是一种新型基因检测技术，主要测序原理是循环微阵列法。其可以预测多种疾病，是将提纯化后的基因组核酸使用高通量测序仪进行测序，获取细菌基因组DNA序列。靶向二代测序（TNGS）可应用于结核分枝杆菌复合体耐药性相关基因突变中，识别耐药性[20]，以粪便为标本并为难以提供呼吸道标本的肺结核患者提供了获得关键诊断信息的机会。宏基因组二代测序（mNGS）由于其全面性，被认为是可能取代传统方法的微生物学方法，是一种很有前途的传染病检测技术，m NGS诊断结核病经meta分析的灵敏度和特异度分别为70%和99%[21]。全基因组测序（WGS）可获得详细的细菌全基因序列,分析耐药基因突变从而预测其耐药表型。WGS可以是结核病耐药监测和确定治疗方案的一种重要方法，虽有明显优势，但是由于操作繁琐且价格高昂，仅在发达国家及低负担结核病国家开展。 3.6 基质辅助激光解吸电离飞行时间质谱技术  MALDI-TOF MS是近年发展起来的一种质谱技术，已成为检测和鉴定多肽、蛋白质、多糖、核苷酸、糖蛋白、高聚物及多种合成聚合物的强有力工具。其主要对微生物的核糖体蛋白组进行分析，形成不同的指纹图谱，与数据库中已知菌种的鉴定谱图进行统计学聚类分析，获得未知样本的鉴定结果。该方法具有灵敏度高、准确度高、分辨率高、图谱简明、质量范围广及速度快等特点，且可大量检测。MALDI-TOF MS诊断肺结核涂阴或无痰肺结核敏感度为68.5%[22]，优于其他方法，有较好的应用前景。与基因芯片相比，MALDI-TOF MS分析时间短、简单、快速、成本低且可以区分结核分枝菌与非结核分枝菌。此外，MALDI-TOF MS也可用于结核分枝杆菌耐药性评估。MALDI-TOF MS技术在MTB药敏检测中表现出良好的灵敏度和特异度，但其无法鉴定不能被培养的细菌，只能鉴定培养阳性的细菌，可以作为临床判断的补充。 4 结核病组学相关研究进展 近年来，结核病组学研究发展迅速，其较高的特异度及灵敏度为进一步快速诊断结核病、区分潜伏性肺结核（LTBI）与活动性肺结核（ATB）提供强有力的支持，为深入了解结核病的发病机制、耐药机制及寻找新的治疗靶点提供了重要的帮助，具有较好的临床应用前景。在结核病的组学研究中，基因组学研究是最早开展的领域之一，通过使用高通量DNA测序和生物信息学来分析整个基因组的功能和结构。在1998年首次对结核分枝杆菌H37Rv菌株进行了全基因组测序，结果显示基因表达产物中40％蛋白质有精确的功能[23]。如今随着技术不断发展，现在已经有许多改良的新方法，前文已详细表述过，现不作过多叙述。 4.1 基于转录组学的生物标志物  转录组学是从RNA水平筛选结核相关的特异性差异表达基因，从而确定生物标志物，可有效预测结核病进展。研究筛选出的3个转录标志(FCGR1A、ZNF296和C1QB)可区分ATB和LTBI[24]，其中AUC为97.3%，为结核病患者靶向治疗提供可能。此外对于耐药检测具有重要意义，2021年的一项研究显示7个基因(TRIM1、9、21、32、33、56、66)能够区分利福平耐药菌株的感染，为RR-TB的发病机制提供了新的实验基础[25]。 4.2 基于蛋白组学的生物标志物  蛋白组学通过分析正常与病理个体之间蛋白质组的差异，为疾病找到新的诊断途径，设计新的治疗靶点，利用蛋白组学筛选结核病生物标志物提高结核病诊断准确性。结核病相关蛋白质可作为潜在的诊断标志物用于区分 LTBI 和ATB。贺仁忠等[26]筛选出8个蛋白标志物，其中Ｒv1441c、Ｒ0494可作为鉴别LTBI和ATB的候选标志物。Yang等[27]筛选出8个蛋白生物标志物（I-TAC、I-309、MIG、颗粒溶素、FAP、MEP1B、弗林蛋白酶和LYVE-1），在区分结核和非结核的验证队列中AUC为0.915，特异度为84%，敏感度为75%。2021年对161名参与者痰液进行分析，发现a-1-酸性糖蛋白两种亚型（即：ORM1和ORM2）在TB抗原检测时显著增加，可能成为肺结核显著的生物标志物[28]。 4.3 基于代谢组学的生物标志物  代谢组学是研究生物系统在特定条件下的整体代谢水平，可揭示结核病发病和耐药过程中代谢产物的变化，从而发现新的治疗靶点。2022一项研究通过GC-MS和LC-MS/MS分析研究结核分枝杆菌感染对血清代谢组的影响，发现了7种代谢物在区分肺结核患者与健康组时表现出较好的性能，可能成为新的生物标志物[29]。Berney等[30]利用代谢组学技术研究发现，宿主体内S-腺苷甲硫氨酸和蛋氨酸的消耗可导致MTB无法增殖和死亡，因此为开发有效的抗结核化疗提供了极好的靶点，但作用机制未完全清楚。代谢组学研究目前比较少，因此可以通过多组学联合分析，更全面地了解结核病菌在感染过程中的作用机制，从而发现更多的治疗靶点。 5 小结 综上，当前结核病的实验室诊断方法种类非常多，从传统的试验方法到现在的测序等，有着全方位的研究和探索。各种方法原理上有较大差异，在结核病诊断中需要综合运用多种技术和手段，包括痰液检测、血液检测、免疫学诊断和分子生物学诊断等。临床需根据各种诊断方法的优缺点选择最佳方法，而诊断技术也需不断发展和完善，找到一个具有高灵敏度、高特异度、更加可靠的方法。对于儿童、免疫功能低下等患者，目前诊断及治疗还需进一步研究。 本文引用来源：王泽锦,胡素侠,戚应杰.结核病实验室诊断方法的现状与进展[J].大医生,2024,9(02). END 免责声明：本文仅作知识交流与分享及科普目的，不涉及商业宣传，不作为相关医疗指导或用药建议。文章如有侵权请联系删除。 TDS2025检测自动化建设与应用论坛主会场，大会第一天下午茶歇前授课时间段预定开始，咨询热线：177 0186 0390。点击图片，查看TDS2024会后报告。

BASEL, Switzerland, Sept. 24, 2024 (GLOBE NEWSWIRE) -- BioVersys AG, a multi-asset, clinical stage biopharmaceutical company focusing on research and development of novel antibacterial products for serious life-threatening infections caused by multi-drug resistant (“MDR”) bacteria, in collaboration with its partners in the AMR Accelerator programme, call for sustainable investment in antimicrobial research and development. Antibiotic resistance is a threat to modern healthcare. Nine European research projects have published in Nature Reviews Drug Discovery an article emphasizing the need to maintain expertise and capability for developing new treatments for infectious diseases, such as those exemplified in the successful European Union’s IMI2 funded TRIC-TB programme. TRIC-TB, successfully reached key milestones, delivering a Phase 2-ready tuberculosis clinical candidate, alpibectir, that is being jointly developed by BioVersys and GSK. The funding that BioVersys as the product developer received, enabled the translation of this exciting new TB therapy into Phase 2a in patients in South Africa. This program now seeks funding to address deadly TB meningitis infections, which predominantly and severely affect children. Together, the nine projects of the AMR Accelerator call on government leaders, the private sector and other stakeholders to invest in the development of new antibiotics and research on antimicrobial resistance (AMR), to secure a sustainable future for large-scale efforts. Dr. Marc Gitzinger, Chief Executive Officer and founder of BioVersys: “The continued innovation for developing new antibiotics fighting AMR is crucial for modern medicine, in high- and low-income countries. There is simply no way around appropriate funding and market incentives for new antibiotics. Efforts led by the European Union, such as the IMI2 programme should continue and be expanded. However, even more important is to act on adequate reimbursement mechanisms for antibiotics, which are life-saving medicines. We hope that successful projects like TRIC-TB demonstrate the success that adequate funding can deliver.” Dr. David Barros-Aguirre, VP and Head of Global Health Medicines R&D Unit, Global Health R&D, GSK: “Now more than ever, there is a need for sustainable funding mechanisms to combat antimicrobial resistance (AMR), which disproportionately impacts people living in lower income countries. We have witnessed the positive impact of pooled procurement mechanisms in supporting equitable access to new vaccines, building resilience into supply chains and contributing to the development of healthy markets. Yet, these mechanisms do not currently exist for many AMR innovative treatment opportunities.” Antimicrobial resistance is recognised as one of the greatest global challenges of our time, undermining healthcare systems that rely heavily on antibiotics to prevent and treat infections. The need for new antibiotics is well-recognized, and on 26 September, the United Nations General Assembly will spotlight this issue in a high-level meeting on AMR. However, the low return on investment in this area has caused many large pharmaceutical companies to leave the field. This has led to a decline in the rate of development of new drugs and therapies for bacterial infections. The broad scope sets the AMR Accelerator apart from other large-scale efforts: the projects have received funding from the European Commission via the Innovative Medicines Initiative (IMI) and pharmaceutical companies that are members of EFPIA. With a total budget of €479 million, the AMR Accelerator has progressed 44 antibacterial programmes over the past 5 years. So far, the effort has resulted in 16 preclinical and clinical candidates, two completed Phase 1 studies, and five ongoing Phase 1 and 2 studies. The continuing success of the AMR Accelerator demonstrates the value of public-private partnerships, replenishing the antibiotics pipeline and providing tools and infrastructure for the global research community. “In TRIC-TB, we combined an agile, fast-moving SME (BioVersys) with the experience and capabilities of a big industry partner (GSK), to develop an anti-TB drug with an entirely new concept. The small consortium size allowed us to move with speed and agility. In 3½ years TRIC-TB completed CTA-enabling and Phase 1 studies allowing the start of a Phase 2a trial despite the impact of the COVID-19 pandemic”, says Michel Pieren, the TRIC-TB project coordinator, from BioVersys. The AMR Accelerator has created critical mass and synergies that have allowed the transfer of assets, knowledge, and expertise between projects. The results are tangible: better and more efficient science, a strengthening of the antibiotic pipeline, and a legacy of research infrastructures that can support the global fight against antibiotic resistance: these include, standardized infection models, non-clinical assays, clinical trial protocols and regulatory compliant processes. However, the key challenge for all nine projects is to ensure the long-term sustainability of assets, infrastructures and expertise. Which in turn requires a commitment from governments and the pharmaceutical industry to long-term investment in antimicrobial research and antibiotics development. Read the article: https://www.nature.com/articles/d41573-024-00138-9 and DOI: 10.1038/d41573-024-00138-9 About the AMR AcceleratorAMR Accelerator programme was launched in 2019, with the aim to accelerate the development of medicines for patients suffering from infections with drug-resistant Mycobacterium tuberculosis, Nontuberculous mycobacteria (NTM), and Gram-negative bacteria, and build capability for antibiotics research and development. The programme is funded by the Innovative Medicines Initiative (IMI). The AMR Accelerator programme includes nine projects: AB-Direct, COMBINE, ERA4TB, GNA NOW, PriMAVeRa, RespiriNTM & RespiriTB, TRIC-TB, and UNITE4TB. Together, the projects have a €479 million budget. The 98 partners represent key stakeholders from academia, industry, small- and medium-sized companies, patient organisations, regulators, and Health Technology Assessment. IMI projects are public-private partnerships, funded in equal parts by the European Union’s Horizon 2020-programme and the pharmaceutical companies that are members of EFPIA. More information: www.amr-accelerator.eu AMR Accelerator portfolio: https://amr-accelerator.eu/amr-accelerator-project-portfolio/ The AMR Accelerator has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under Grant Agreements No 853967 I 853989 I 853979 I 853932 I 853800 I 853903 I 853976 I 101007873 I 101034420. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. ERA4TB receives additional support from Global Alliance for TB Drug Development, Bill & Melinda Gates Foundation and University of Dundee. UNITE4TB receives additional support from Deutsches Zentrum für Infektionsforschung e. V. (DZIF), and Ludwig-Maximilians-Universität München (LMU). EFPIA/AP contribute to 50% of funding, whereas the contribution of DZIF and the LMU University Hospital Munich has been granted by the German Federal Ministry of Education and Research. Disclaimer: This text reflects the author’s view. Neither IMI nor the European Union, EFPIA or any other third parties are responsible for any use that may be made of the information contained herein. The COMBINE project has a coordinating role in the AMR Accelerator programme. For more information, please contact Anders Karlén, Professor of Computer-Aided Drug Design, Uppsala University & project coordinator, COMBINE. E-mail: anders.karlen@uu.se or Marie Olliver, Alliance manager COMBINE, Uppsala University. E-mail: marie.olliver@uu.se. About TRIC-TBTRIC-TB successfully completed the Phase 1 study with alpibectir (BVL-GSK098), a small molecule potentiating the activity of ethionamide. It is hoped alpibectir would allow lower doses of ethionamide thus minimizing dose-dependent side effects and, it is hoped, improving patient compliance. In laboratory tests, the combination of alpibectir/ethionamide (AlpE) is rapidly bactericidal, overcomes MDR and Eto-resistance, and shows the potential to become an important building block in novel regimens in TB endemic countries. AlpE is currently tested in a Phase 2a proof-of-concept study (NCT05473195). TRIC-TB has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under Grant Agreement No 853800. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA companies’ in-kind contribution. For more information, please contact Michel Pieren, Clinical Program Team Leader, BioVersys & TRIC-TB project coordinator. E-mail: michel.pieren@bioversys.com About GSKGSK is a global biopharma company with a purpose to unite science, technology, and talent to get ahead of disease together. Find out more at gsk.com About BioVersysBioVersys AG is a multi-asset, clinical stage biopharmaceutical company focused on identifying, developing and commercializing novel antibacterial products for serious life-threatening infections caused by multi-drug resistant (“MDR”) bacteria. Derived from the company’s two internal technology platforms (TRIC and Ansamycin Chemistry), candidates are designed and developed to overcome resistance mechanisms, block virulence production and directly affect the pathogenesis of harmful bacteria towards the identification of new treatment options in the antimicrobial and microbiome fields. This enables BioVersys to address the high unmet medical need for new treatments against life-threatening resistant bacterial infections and bacteria-exacerbated chronic inflammatory microbiome disorders. The company’s most advanced research and development programs address nosocomial infections of Acinetobacter baumannii (BV100, Phase 2), and tuberculosis (alpibectir, Phase 2a, in collaboration with GlaxoSmithKline (GSK) and a consortium of the University of Lille, France). BioVersys is located in the biotech hub of Basel, Switzerland. BioVersys contact Sylvia Mundt, Executive Assistant to CEO, Tel. +41 61 633 22 50 ; Mail : IR@bioversys.com Website: www.bioversys.com https://twitter.com/Bioversyshttps://www.linkedin.com/company/bioversys-ag