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An Update on the Clinical Pipelines of New Antibacterial Drugs Developed in China

Engineering 2024年第7期38卷 52-68页

作者： Xinyi Yang congran li Xiukun Wang Zhonghui Zheng Peiyi Sun Chunjie Xu Luni Chen Jiandong Jiang Staffan Normark Birgitta Henriques-Normark Xuefu You Beijing Key Laboratory of Antimicrobial Agents/Laboratory of Pharmacology Institute of Medicinal BiotechnologyChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100050China Division for Medicinal Microorganism-Related Strains CAMS Collection Center of Pathogenic MicroorganismsChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100050China State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Medicinal BiotechnologyChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100050China Shandong Xinhua Pharmaceutical Co. Ltd.Zibo 255005China Department of Microbiology Tumor and Cell BiologyKarolinska InstitutetStockholm SE-17177Sweden State Key Laboratory of Bioactive Substances and Function of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100050China Institute of Medicinal Biotechnology Chinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100050China Clinical Microbiology Karolinska University HospitalBioclinicumStockholm SE-17176Sweden

Antibacterial resistance is a global health threat that requires further concrete action on the part of all *** this context,one of the biggest concerns is whether enough new antibacterial drugs are being discovered and *** several high-quality reviews on clinical antibacterial drug pipelines from a global perspective were published recently,none provides comprehensive information on original antibacterial drugs at clinical stages in *** this review,we summarize the latest progress of novel antibacterial drugs approved for marketing and under clinical evaluation in China since *** was obtained by consulting official websites,searching commercial databases,retrieving literature,asking personnel from institutions or companies,and other means,and a considerable part of the data covered here has not been included in other *** of June 30,2023,a total of 20 antibacterial projects from 17 Chinese pharmaceutical companies or developers were identified and *** them,two new antibacterial drugs that belong to traditional antibiotic classes were approved by the National Medical Products Administration(NMPA)in China in 2019 and 2021,respectively,and 18 antibacterial agents are in clinical development,with one under regulatory evaluation,five in phase-3,six in phase-2,and six in *** of the clinical candidates are new analogs or monocomponents of traditional antibacterial pharmacophore types,including two dual-acting hybrid antibiotics and a recombinant antibacterial ***,despite there being 17 antibacterial clinical candidates,our analysis indicates that there are still relatively few clinically differentiated antibacterial agents in stages of clinical development in ***,Chinese pharmaceutical companies and institutions will develop more innovative and clinically differentiated candidates with good market potential in the future research and development(R&D)of original antibacterial drugs.

关键词： Antimicrobial resistance New antibiotics Clinical pipelines WHO priority pathogens National Mega-Project for Innovative Drugs

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Coagulation factors: a novel class of endogenous host antimicrobial proteins against drug-resistant gram-negative bacteria

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Signal Transduction and Targeted Therapy 2019年第1期4卷 238-239页

作者： congran li Xuefu You Beijing Key Laboratory of Antimicrobial Agents Institute of Medicinal BiotechnologyChinese Academy of Medical Sciences&Peking Union Medical College100050 BeijingChina

In a recent study published in Cell Research,*** Song’s group reported the potent antibacterial activity of three coagulation factors(VII,IX,and X)against gram-negative bacteria and hence discovered a novel class of endogenous host antimicrobial proteins.1 At present,antimicrobial resistance(AMR)poses significant challenges for clinical care and seriously threatens human health.2,3 Among the clinical pathogens,gram-negative bacteria are particularly problematic in terms of drug resistance because their lipopolysaccharide(LPS)-rich outer membrane reduces cellular permeability and acts as a target for antibacterial resistance development.

关键词： hence outer endogenous

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Validated LC–MS/MS method for determination of YH-8, a novel PKnB inhibitor, in rat plasma and its application to pharmacokinetic study

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Acta Pharmaceutica Sinica B 2015年第5期5卷 467-472页

作者： Qianqian Zhai Jing Pang Guoqing li congran li Xinyi Yang liyan Yu Yucheng Wang Jian li Xuefu You Institute of Medicinal Biotechnology Chinese Academy of Medical Sciences and Peking Union Medical College Key Laboratory of Sustainable Development of Marine Fisheries Ministry of Agriculture Yellow Sea Fisheries Research Institute Chinese Academy of Fishery Sciences

(E)-Methyl-4-aryl-4-oxabut-2-enoate(YH-8) is a novel PKn B protein kinase inhibitor with good anti-tuberculosis activity. To evaluate its pharmacokinetics in rats, a sensitive and selective high performance liquid chromatography–tandem mass spectrometric(LC–MS/MS) method has been developed and validated for the quantification of YH-8 in rat plasma for the first time. Samples were pre-treated using a liquid–liquid extraction with ethyl acetate and the chromatographic separation was performed on a C18 column by gradient elution with methanol–water as the mobile phase. YH-8 was detected using a tandem mass spectrometer in positive selected reaction monitoring(SRM) mode. Method validation revealed good linearity over the range of1–500 ng/m L for YH-8 with a lower limit of quantification(LLOQ) of 1 ng/m L. Intra- and inter-day precision of YH-8 assay in rat plasma samples were 2.0%–6.8%, with accuracy of the method being 100.69%–106.18%.Stability test showed that when spiked into rat plasma, YH-8 was stable for 12 h at room temperature, for up to15 days at -70℃, and after three freeze-thaw cycles. Extracted samples were found to be stable over 12 h in an auto-sampler. The method was successfully applied to the pharmacokinetic study of YH-8 in rats after oral administration at 100 mg/kg and 200 mg/kg.

关键词： YH-8 LC–MS/MS Pharmacokinetics Rat plasma Method validation

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研发项目进度精细化管理

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船舶标准化工程师 2024年第4期57卷 16-19页

作者：李聪冉侯春彩杨申昊陶文健邯郸净化设备研究所河北邯郸056000

为提高研发效率,加强进度管理,对研发项目进度管理存在的问题进行分析,并使用产品生命周期管理系统软件和看板管理工具从项目节点控制和项目计划管理等两方面对项目进度进行精细化管理。研究表明:该精细化管理方法对项目进度管理具有积... 详细信息

为提高研发效率,加强进度管理,对研发项目进度管理存在的问题进行分析,并使用产品生命周期管理系统软件和看板管理工具从项目节点控制和项目计划管理等两方面对项目进度进行精细化管理。研究表明:该精细化管理方法对项目进度管理具有积极意义,研发项目节点达成率有大幅提高。研究成果可为研发项目进度精细化管理提供一定参考。

关键词：研发项目进度管理项目节点项目计划看板管理

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Polymyxin resistance caused by large-scale genomic inversion due to IS26 intramolecular translocation in Klebsiella pneumoniae

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药学学报:英文版 2023年第9期13卷 3678-3693页

作者： Haibin li Lang Sun Han Qiao Zongti Sun Penghe Wang Chunyang Xie Xinxin Hu Tongying Nie Xinyi Yang Guoqing li Youwen Zhang Xiukun Wang Zhuorong li Jiandong Jiang congran li Xuefu You Beijing Key Laboratory of Antimicrobial Agents Institute of Medicinal BiotechnologyChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100050China Institute of Medicinal Biotechnology Chinese Academy of Medical Science&Peking Union Medical CollegeBeijing 100050China State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Science&Peking Union Medical CollegeBeijing 100050China

Polymyxin B and polymyxin E(colistin)are presently considered the last line of defense against human infections caused by multidrug-resistant Gram-negative organisms such as carbapenemase-producer Enterobacterales,Acinetobacter baumannii,and Klebsiella *** resistance to this last-line drugs is a major public health threat and is rapidly *** S2(S2)is a polymyxin B analogue previously synthesized in our institute with obviously high antibacterial activity and lower toxicity than polymyxin B and *** predict the possible resistant mechanism of S2for wide clinical application,we experimentally induced bacterial resistant mutants and studied the preliminary resistance ***-S,a resistant mutant of *** ATCC BAA-2146(Kpn2146)induced by S2,was analyzed by whole genome sequencing,transcriptomics,mass spectrometry and complementation ***,large-scale genomic inversion(LSGI)of approximately 1.1 Mbp in the chromosome caused by IS26mediated intramolecular transposition was found in Mut-S,which led to mgrB truncation,lipid A modification and hence *** resistance can be complemented by plasmid carrying intact *** same mechanism was also found in polymyxin B and colistin induced drug-resistant mutants of Kpn2146(Mut-B and Mut-E,respectively).This is the first report of polymyxin resistance caused by IS26 intramolecular transposition mediated mgrB truncation in chromosome in *** findings broaden our scope of knowledge for polymyxin resistance and enriched our understanding of how bacteria can manage to survive in the presence of antibiotics.

关键词： Klebsiella pneumoniae Polymyxin resistance mgrB IS26 Whole genome sequencing Structural variation Inversion

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In vitro and in vivo activity of D-serine in combination with β-lactam antibiotics against methicillin-resistant Staphylococcus aureus

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Acta Pharmaceutica Sinica B 2019年第3期9卷 496-504页

作者： Qing Wang Yuemeng Lv Jing Pang Xue li Xi Lu Xiukun Wang Xinxin Hu Tongying Nie Xinyi Yang Yan Q.Xiong Jiandong Jiang congran li Xuefu You Beijing Key Laboratory of Antimicrobial Agents Institute of Medicinal BiotechnologyChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing100050China Los Angeles Biomedical Research Institute Harbor-UCLA Medical CenterTorranceCA90502USA David Geffen School of Medicine at UCLA Los AngelesCA90095USA State Key Laboratory of Bioactive Substances and Function of Natural Medicine Institute of Materia MedicaChinese Academy ofMedical Sciences and Peking Union Medical CollegeBeijing100050China

As D-amino acids play important roles in the physiological metabolism of bacteria,combination of D-amino acids with antibiotics may provide synergistic antibacterial activity. The aim of the study was to evaluate in vitro and in vivo activity of D-serine alone and in combination withβ-lactams against methicillin-resistant Staphylococcus aureus(MRSA) strains, and to explore the possible sensitization mechanisms. The activity of D-serine, β-lactams alone and in combinations was evaluated both in vitro by standard MICs, time–kill curves and checkerboard assays, and in vivo by murine systemic infection model as well as neutropenic thigh infection model. An in vitro synergistic effect was demonstrated with the combination of D-serine and β-lactams against MRSA standard and clinical ***, the combinations enhanced the therapeutic efficacy in the animal models as compared toβ-lactam alone groups. Initial mechanism study suggested possible revision of D-alanine-D-alanine residue to D-alanine-D-serine in peptidoglycan by adding of D-alanine in the medium, which may cause decreased affinity to PBPs during transpeptidation. In conclusion, D-serine had synergistic activity in combination with β-lactams against MRSA strains both in vitro and in vivo. Considering the relatively good safety of D-serine alone or in combination with β-lactams, D-serine is worth following up as new anti-MRSA infection strategies.

关键词： MRSA D-Serine β-Lactams Combination Synergistic effect

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Genetic basis of high level aminoglycoside resistance in Acinetobacter baumannii from Beijing,China

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Acta Pharmaceutica Sinica B 2014年第4期4卷 295-300页

作者： Lu Nie Yuemeng Lv Min Yuan Xinxin Hu Tongying Nie Xinyi Yang Guoqing li Jing Pang Jingpu Zhang congran li Xiukun Wang Xuefu You Institute of Medicinal Biotechnology Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China The First People's Hospital of Foshan Foshan 528000China State Key Laboratory for Infectious Diseases Prevention and Control National Institute for Communicable Disease Control and PreventionChinese Center for Disease Control and PreventionBeijing 102206China

The objective of this study was to investigate the genetic basis of high level aminoglycoside resistance in Acinetobacter baumannii clinical isolates from Beijing,China.173 *** clinical isolates from hospitals in Beijing from 2006 to 2009 were first subjected to high level aminoglycoside resistance(HLAR,MIC to gentamicin and amikacin>512 mg/mL)phenotype selection by broth microdilution *** strains were then subjected to genetic basis analysis by PCR detection of the aminoglycoside modifying enzyme genes(aac(3)-Ⅰ,aac(3)-Ⅱc,aac(60)-Ⅰb,aac(60)-Ⅱ,aph(4)-Ⅰa,aph(30)-Ⅰ,aph(30)-Ⅱb,aph(30)-Ⅲa,aph(30)-Ⅵa,aph(2″)-Ⅰb,aph(2″)-Ⅰc,aph(2″)-Ⅰd,ant(2″)-Ⅰa,ant(3″)-Ⅰand ant(40)-Ⅰa)and the 16S rRNA methylase genes(armA,rmtB and rmtC).Correlation analysis between the presence of aminoglycoside resistance gene and HLAR phenotype were performed by *** 102(58.96%)HLAR isolates were *** HLAR rates for year 2006,2007,2008 and 2009 were 52.63%,65.22%,51.11%and 70.83%,*** modifying enzyme genes(aac(3)-Ⅰ,detection rate of 65.69%;aac(60)-Ⅰb,detection rate of 45.10%;aph(30)-Ⅰ,detection rate of 47.06%;aph(30)-Ⅱb,detection rate of 0.98%;ant(3″)-Ⅰ,detection rate of 95.10%)and one methylase gene(armA,detection rate of 98.04%)were detected in the 102 *** with aac(3)-Ⅰ+aac(60)-Ⅰ+þant(3″)-Ⅰ+armA(detection rate of 25.49%),aac(3)-Ⅰ+aph(30)-Ⅰ+ant(3″)-Ⅰ+armA(detection rate of 21.57%)and ant(3″)-Ⅰ+armA(detection rate of 12.75%)being the most prevalent gene *** values of chi-square tests showed correlation of armA,ant(3″)-Ⅰ,aac(3)-Ⅰ,aph(30)-Ⅰand aac(60)-Ⅰb with *** had significant correlation(contingency coefficient 0.685)and good contingency with HLAR(kappa 0.940).The high rates of HLAR may cause a serious problem for combination therapy of aminoglycoside with β-lactams against *** *** armA was reported to be able to cause high level aminoglycoside resistance to most of the clinical important aminoglycosides(gentamicin,ami

关键词： Acinetobacter baumannii HLAR Aminoglycoside modifying enzyme 16S rRNA methylase Correlation analysis

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Combined therapy of Neuropilin-1 positive T cells with low-dose rapamycin prolongs fully MHC-mismatched cardiac allograft survival in mice

Combined therapy of Neuropilin-1 positive T cells with low-d...

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2013中国器官移植大会

作者： Qing Yuan Hailong Jin congran li li Xiao liang Xu Xing Wei Xiang li Zhouli li Bingyi Shi Ming Cai Organ Transplant Institution of PLA The 309th Hospital of PLA

Immunosuppressive cell based therapies using CD4CD25Foxp3regulatory T(Treg)cells and tolerogenic dendritic cells have been reported to be efficient in promoting tolerance in experimental as well as in preclinical *** Tregs,other immunosuppressive T cells could also be found among CD4CD25cells,as well as TCRαβCD3CD4 CD8 NK1.1 double negative) T *** the specific subpopulation of these immunosuppressive T cells requires further investigation,one of the most urgent needs in translational use of these cells is an efficient and reliable way to isolate ***-1(Nrp1),a type 1 transmembrane protein originally identified to be involved in axonal guidance and in angiogenesis,has been reported to be constitutively expressed on murine Tregs serving as a surface ***1 has recently been imolicated in the regulation of CD4 T—cell immune

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CO_(2)汽提工艺尿素装置低压系统改造总结

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氮肥技术 2023年第6期44卷 6-8,26页

作者：王朝亮李丛然海洋石油富岛有限公司海南东方572600

本文简要介绍尿素装置因低压甲铵冷凝器换热能力不足而引发的一系列问题,包括解吸水解负荷高、高压转化率低、液位储槽气相管线堵塞和高能耗等,通过采取措施,但问题一直未得到根本解决。2022年检修,对低压系统进行改造,增加了一台串联... 详细信息

本文简要介绍尿素装置因低压甲铵冷凝器换热能力不足而引发的一系列问题,包括解吸水解负荷高、高压转化率低、液位储槽气相管线堵塞和高能耗等,通过采取措施,但问题一直未得到根本解决。2022年检修,对低压系统进行改造,增加了一台串联换热器,对改造后的效果进行分析并指出改造后出现的问题。

关键词：低压系统问题原因改造效果

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肾移植术后巨细胞病毒感染及其与NK细胞亚群相关性的初步探讨

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器官移植 2020年第6期11卷 685-691页

作者：孙曙刘志佳李响金海龙李聪然陈昌庆石炳毅中国人民解放军第八医学中心全军器官移植研究所北京100091

目的探讨自然杀伤(NK)细胞亚群在肾移植术后巨细胞病毒(CMV)感染受者中的变化趋势。方法回顾性分析92例肾移植受者的临床资料,将肾移植受者分为CMV感染组(43例)、CMV感染恢复组(13例)、肾功能稳定组(15例)、排斥反应组(11例)和其他感染... 详细信息

目的探讨自然杀伤(NK)细胞亚群在肾移植术后巨细胞病毒(CMV)感染受者中的变化趋势。方法回顾性分析92例肾移植受者的临床资料,将肾移植受者分为CMV感染组(43例)、CMV感染恢复组(13例)、肾功能稳定组(15例)、排斥反应组(11例)和其他感染组(10例);另外选取健康成人志愿者作为健康对照组(15名)。观察并比较各组外周血NK细胞比例,及NK细胞中CD226和CD16的表达比例和平均荧光强度(MFI)。结果CMV感染组NK细胞比例为4.9%(2.2%,11.5%),CMV感染恢复组NK细胞比例为3.7%(2.3%,6.5%),CMV感染组和CMV感染恢复组NK细胞比例均低于其他各组(均为P<0.05)。CMV感染组NK细胞中CD226和CD16的表达比例低于健康对照组和肾功能稳定组(均为P<0.05)。CMV感染恢复组NK细胞中CD226和CD16的表达比例均高于CMV感染组(均为P<0.05)。CMV感染组CD226和CD16的MFI均低于健康对照组(均为P<0.05)。CMV感染恢复组CD226和CD16的MFI均高于CMV感染组(均为P<0.05)。结论CMV感染期NK细胞中CD226和CD16的表达比例及MFI下调,而在CMV感染恢复期上调,提示NK细胞表达的CD226、CD16与CMV感染的病程密切相关。

关键词：自然杀伤细胞肾移植排斥反应巨细胞病毒感染免疫抑制剂 CD226 CD16

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