While drug-susceptible tuberculosis (TB) disease in children currently requires four to six months of treatment, most children may be able to be cured with a shorter treatment of more powerful drugs. Shorter treatment may be easier for children to tolerate and finish as well as ease caregiver strain from managing treatment side effects and supporting children over many months. The primary objective of this study is to evaluate if a 2-month regimen (including isoniazid (H), rifapentine (P), pyrazinamide (Z) and moxifloxacin (M)) is as safe and effective as a 4- to 6-month regimen (isoniazid, rifampicin (R), pyrazinamide, ethambutol (E)) in curing drug-susceptible TB disease in children under 10 years old. The study is also evaluating the safety of the HPZM in children with and without HIV.

开始日期2024-11-15

申办/合作机构

The Johns Hopkins University

NCT06441006 / Not yet recruiting临床3期IIT

Program for Rifampicin-Resistant Disease With Stratified Medicine for Tuberculosis (PRISM-TB)

PRISM-TB is an international, multicenter, open-label, randomized, controlled, pragmatic, stratified medicine, treatment shortening, noninferiority Phase 3 clinical trial for fluoroquinolone-susceptible multidrug-resistant/rifampin-resistant pulmonary tuberculosis (FQ-S MDR/RR-TB).
The trial objective is to evaluate whether stratified medicine treatment strategies for FQ-S MDR/RR-TB, defined by a pre-specified risk stratification algorithm, have noninferior efficacy to a one-size-fits-all control regimen (the local standard-of-care [SOC] regimen consistent with preferred regimen(s) in international guidelines), as measured by TB-related unfavorable outcomes at Week 73.

开始日期2024-11-01

申办/合作机构

The University of California, San Francisco

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项与 Topoisomerase IV 相关的文献（医药）

2024-11-01·European Journal of Medicinal Chemistry

Improved N-phenylpyrrolamide inhibitors of DNA gyrase as antibacterial agents for high-priority bacterial strains

Article

作者: Ilaš, Janez ; Jovanovic, Milija ; Senerovic, Lidija ; Peršolja, Peter ; Tammela, Päivi ; Durcik, Martina ; Pál, Csaba ; Onali, Alessia ; Dernovšek, Jaka ; Benedetto Tiz, Davide ; Czikkely, Márton Simon ; Hrast Rambaher, Martina ; Cotman, Andrej Emanuel ; Kikelj, Danijel ; Tomašič, Tihomir ; Zega, Anamarija ; Szili, Petra Éva ; Peterlin Mašič, Lucija ; Cruz, Cristina D. ; Zidar, Nace ; Cruz, Cristina D ; Skok, Žiga

In this work, we describe an improved series of N-phenylpyrrolamide inhibitors that exhibit potent activity against DNA gyrase and are highly effective against high-priority gram-positive bacteria. The most potent compounds show low nanomolar IC₅₀ values against Escherichia coli DNA gyrase, and in addition, compound 7c also inhibits E. coli topoisomerase IV in the nanomolar concentration range, making it a promising candidate for the development of potent dual inhibitors for these enzymes. All tested compounds show high selectivity towards the human isoform DNA topoisomerase IIα. Compounds 6a, 6d, 6e and 6f show MIC values between 0.031 and 0.0625 μg/mL against vancomycin-intermediate S. aureus (VISA) and Enterococcus faecalis strains. Compound 6g shows an inhibitory effect against the methicillin-resistant S. aureus strain (MRSA) with a MIC of 0.0625 μg/mL and against the E. faecalis strain with a MIC of 0.125 μg/mL. In a time-kill assay, compound 6d showed a dose-dependent bactericidal effect on the MRSA strain and achieved bactericidal activity at 8 × MIC after 8 h. The duration of the post-antibiotic effect (PAE) on the MRSA strain for compound 6d was 2 h, which corresponds to the PAE duration for ciprofloxacin. The compounds were not cytotoxic at effective concentrations, as determined in an MTS assay on the MCF-7 breast cancer cell line.

2024-10-08·Proceedings of the National Academy of Sciences

Experimental localization of metal-binding sites reveals the role of metal ions in type II DNA topoisomerases

Article

作者: Najmudin, Shabir ; Pan, Xiao-Su ; Wang, Beijia ; Govada, Lata ; Mykhaylyk, Vitaliy ; Orr, Christian ; Chayen, Naomi E. ; Fisher, L. Mark ; Sanderson, Mark R. ; Wagner, Armin

Metal ions have important roles in supporting the catalytic activity of DNA-regulating enzymes such as topoisomerases (topos). Bacterial type II topos, gyrases and topo IV, are primary drug targets for fluoroquinolones, a class of clinically relevant antibacterials requiring metal ions for efficient drug binding. While the presence of metal ions in topos has been elucidated in biochemical studies, accurate location and assignment of metal ions in structural studies have historically posed significant challenges. Recent advances in X-ray crystallography address these limitations by extending the experimental capabilities into the long-wavelength range, exploiting the anomalous contrast from light elements of biological relevance. This breakthrough enables us to confirm experimentally the locations of Mg 2+ in the fluoroquinolone-stabilized Streptococcus pneumoniae topo IV complex. Moreover, we can unambiguously identify the presence of K + and Cl - ions in the complex with one pair of K + ions functioning as an additional intersubunit bridge. Overall, our data extend current knowledge on the functional and structural roles of metal ions in type II topos.

2024-10-01·Biomedicine & Pharmacotherapy

Antibacterial and anti-biofilm activities of new fluoroquinolone derivatives coupled with nitrogen-based heterocycles

Article

作者: Markowska, Kinga ; Stefańska, Joanna ; Struga, Marta ; Roszkowski, Piotr ; Bielenica, Anna ; Koliński, Michał ; Chrzanowska, Alicja ; Kmiecik, Sebastian ; Majewska, Anna ; Pituch, Hanna

We report the design, synthesis, and antimicrobial evaluation of a series of ciprofloxacin (CP) conjugates coupled with nitrogen-containing heterocycles. In vitro screening of these new hybrid compounds (1-13) against a panel of planktonic bacterial strains highlighted thiazolyl homologs 6 and 7 as the most promising candidates for further investigation. These derivatives demonstrated potent growth-inhibitory activity against various standard and clinical isolates, with minimum inhibitory concentrations (MICs) ranging from 0.05 to 0.4 µg/ml, which are higher or comparable to the reference fluoroquinolone. Both compounds effectively inhibited biofilm formation by selected staphylococci across all tested concentrations (1-8 x MIC), displaying greater efficacy at higher doses compared to CP alone. Notably, conjugate 7 also significantly eradicated existing biofilms formed by S. aureus of various origin. Molecular docking studies revealed that conjugate 7 engages in a broader range of interactions with DNA gyrase and DNA topoisomerase IV than CP, suggesting stronger binding affinity and enhanced flexibility. This may contribute to its potential in overcoming bacterial resistance mechanisms. The above findings indicate compound 7 as a promising candidate for clinical development.

项与 Topoisomerase IV 相关的新闻（医药）

2024-10-16

·药明康德

有望成为20年来首款！GSK潜在"first-in-class"小分子疗法获FDA优先审评资格

▎药明康德内容团队编辑 GSK今天宣布，美国FDA已接受其潜在"first-in-class"口服抗生素gepotidacin的新药申请（NDA），用于治疗患有单纯性尿路感染（uUTI，也称为急性膀胱炎）成年或青少年（≥12岁）女性患者，患者体重须≥40公斤。FDA授予该申请优先审评资格，并预计在2025年3月26日前完成审评。根据新闻稿，若获批，gepotidacin将成为20多年来首个用于治疗uUTI的新型口服抗生素药物。超过一半的女性一生中会罹患uUTI，其中约30%的女性会发生复发。由于耐药细菌引起的uUTI病例不断增加，可能导致更高的治疗失败率，因此急需开发新的治疗方法。该新药申请得到了关键性3期EAGLE-2和EAGLE-3试验积极结果的支持。在这些研究中，与目前uUTI标准疗法nitrofurantoin抗生素相比，gepotidacin在治疗确诊的uUTI成年与青少年女性患者中展现非劣效性，这些患者已知对nitrofurantoin应答。 ▲Gepotidacin分子结构（图片来源：PubChem）在EAGLE-3试验中，gepotidacin与活性对照药物相比具有统计学显著优势，58.5%（n=162/277）的gepotidacin组患者治疗成功，而此数值在活性对照药物组中为43.6%（n=115/264，差异14.6%，95% CI：6.4~22.8）。在EAGLE-2试验中，50.6%（n=162/320）的gepotidacin组患者显示出治疗成功，而此数值在活性对照组中为47.0%（n=135/287，差异4.3%，95% CI：-3.6~12.1）。 Gepotidacin在EAGLE-2和EAGLE-3试验中的安全性和耐受性结果与先前试验一致。 Gepotidacin是一款具有全新作用机制的抗生素，它可以口服，并具有双重作用机制，能同时选择性地结合并抑制DNA促旋酶和DNA拓扑异构酶IV，从而诱发在复制进程的DNA发生单链断裂，进而达到杀死病原体的目的。 ▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放参考资料： [1] Gepotidacin accepted for priority review by US FDA for treatment of uncomplicated urinary tract infections in female adults and adolescents. Retrieved October 16, 2024 from https://www.gsk.com/en-gb/media/press-releases/gepotidacin-accepted-for-priority-review-by-us-fda-for-treatment-of-uncomplicated-urinary-tract-infections-in-female-adults-and-adolescents/ 免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。分享，点赞，在看，聚焦全球生物医药健康创新

优先审批临床结果临床3期

2024-04-17

·Firstwordpharma

GSK shares promising data for gepotidacin antibiotic in gonorrhoea

GSK on Wednesday spelled out more details on a positive Phase III trial of its investigational antibiotic gepotidacin as a potential new treatment for uncomplicated urogenital gonorrhea.The roughly 600-patient EAGLE-1 trial, which was toplined earlier this year, met its primary endpoint. Gepotidacin achieved a 92.6% microbiological success rate and demonstrated non-inferiority to the leading combination of intramuscular ceftriaxone plus oral azithromycin, which had 91.2% success rates.Safety and tolerability of gepotidacin in EAGLE-1 was similar to findings from earlier Phase I and II trials. Adverse events were typically mild or moderate, with the most common side effects being gastrointestinal. There was one severe and one serious event in the gepotidacin arm, although both cases were considered unrelated to the drug. Results will be presented at the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) at the end of the month.Rising drug-resistant infectionsChris Corsico, head of development at GSK, said, "These results highlight the potential of gepotidacin as a new oral treatment option given the rising incidence of gonorrhoea worldwide, including drug-resistant infections." Each year, about 82 million new cases of gonorrhoea occur worldwide, and there has been a 118% increase in reported cases in the US from 2009 to 2021, with about half resistant to at least one antibiotic.Analysts at Barclays recently highlighted gepotidacin's dual-targeting mechanism against the DNA gyrase and topoisomerase IV enzymes as a key advantage in overcoming antibiotic resistance. They project peak sales could reach £801 million ($996 million) for the first-in-class antibiotic, if approved.Beyond EAGLE-1, GSK has also reported positive Phase III data from the EAGLE-2 and EAGLE-3 trials evaluating gepotidacin for uncomplicated urinary tract infections (uUTI). The company is gearing up for regulatory submissions; it expects to file for uUTI next half, followed by a submission for urogenital gonorrhoea in 2025.GSK had previously targeted its uUTI filing by mid-2023, but told FirstWord on Wednesday that it is "working with the FDA, ahead of submission, to include additional non-clinical data requested by FDA to support its filing package."Elsewhere in its antimicrobials pipeline, GSK struck a licencing deal with Spero Therapeutics in 2022 to add tebipenem HBr, a late-stage antibiotic and potential treatment for complicated UTIs. And last year, it partnered with Scynexis on the antifungal Brexafemme (ibrexafungerp) to treat vulvovaginal candidiasis (VVC) and reduce the incidence of recurrent VVC.

临床结果临床3期临床1期合格传染病产品

2024-03-30

·医药地理

【好文推荐】氢氯噻嗪-氟胞嘧啶共晶的制备、表征及溶解性考察

未经授权，不得转载氢氯噻嗪-氟胞嘧啶共晶的制备、表征及溶解性考察Preparation, Characterization and Solubility Investigation ofHydrochlorothiazide-flucytosine Cocrystal邓雪珍，陈乐乐，谭雨梦，钱坤*，杨婕(江西中医药大学药学院，江西南昌 330004)摘要：为提高氢氯噻嗪(1) 的水溶性和改善氟胞嘧啶(2) 的引湿性，该文制备了1-2 共晶。应用单晶X 射线衍射、粉末X 射线衍射、傅里叶变换红外光谱、热重和差示扫描量热等方法对其进行了表征，并研究了1-2 共晶的溶解性和引湿性。结果表明，与1 相比，1-2 共晶中的1 在盐酸(pH 1.2)、磷酸盐缓冲液(pH 6.8) 和纯水(pH 7.0) 中的平衡溶解度和特性溶出速率均得到提高。并且，1-2 共晶在25 ℃和相对湿度95％的条件下未发生增重。研究结果表明所制备的1-2 共晶增加了1 的溶解性，并减轻了2 的引湿性，为提高难溶性药物溶解性的研究提供了参考。关键词：氢氯噻嗪；氟胞嘧啶；共晶；溶解性；引湿性以下为文章节选药物共晶是由API 与其他一种或一种以上的共晶形成物(cocrystal former，CCF) 或药物以一定比例通过非共价键结合于一个晶格内并堆积而成的物质状态[1]。自首个用于治疗心脑血管疾病的共晶药物“沙库巴曲+ 缬沙坦”获FDA 批准上市以来，药物共晶受到了广泛关注[2—3]。随着对药物共晶及API 理化性质的深入研究，共晶技术被广泛用于改善API 因其原有结构而导致的生物利用度低、渗透性差、溶解性差、稳定性低等的研究之中[4—5]。氢氯噻嗪(hydrochlorothiazide，1，图1A) 是一种利尿性抗高血压药，被广泛用于治疗浮肿和高血压，属于低溶解性和低渗透性的BCS Ⅳ类药物，体内生物利用度低[6—7]。氟胞嘧啶(flucytosine，2，图1B) 是一种常用的抗真菌药，可用于治疗念珠菌和隐球菌感染，但其稳定性较差，易因水合作用导致晶型改变，不利于生产和贮存[8—9]。本研究采用溶剂挥发法制备1-2 共晶，并通过平衡溶解度、特性溶出速率(intrinsic dissolution rate，IDR) 和引湿性试验考察共晶是否改善了1 的溶解性和2 的引湿性，以期为提高难溶性药物1 的溶解性和增加2 的片剂成药性研究提供数据参考。↑长按二维码阅读全文基金项目：国家自然科学基金资助项目(22165014)、江西省2022年度研究生创新专项资金项目(YC2022-s856)、中药炮制技术的传承与创新项目(CXTD22003)作者简介：邓雪珍(1998—)，女，硕士研究生，专业方向：药物化学。通信作者：钱坤(1979—)，男，副教授，博士，从事药物共晶的研究。E-mail：qiankun@jxutcm.edu.cn文章详情欢迎登录《中国医药工业杂志》官网查看。END如需获取更多数据洞察信息或公众号内容合作，请联系医药地理小助手微信号：pharmadl001

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