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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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Discovery and structure-activity relationship studies of novel tetrahydro-β-carboline derivatives as apoptosis initiators for treating bacterial infections

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Journal of Integrative Agriculture 2024年第4期23卷 1259-1273页

作者： Shanshan Su Hongwu Liu Junrong Zhang Puying Qi Yue Ding Ling Zhang Linli Yang Liwei Liu Xiang Zhou Song Yang National key laboratory of Green Pesticide/key laboratory of Green Pesticide and Agricultural Bioengineering Ministry of Education/Center for R&D of Fine ChemicalsGuizhou UniversityGuiyang 550025China

Developing and excavating new agrochemicals with highly active and safe is an important tactic for protecting crop health and food *** this paper,to discover the new bactericide candidates,we designed,prepared a new type of1,2,3,4-tetrahydro-β-carboline(THC)derivatives and evaluated the in vitro and in vivo bioactivities against the Xanthomonas oryzae ***(Xoo),Xanthomonas axonopodis ***(Xac),and Pseudomonas syringae ***(Psa).The in vitro bioassay results exhibited that most title molecules possessed good activity toward the three plant pathogenic bacteria,the compound A17 showed the most active against Xoo and Xac with EC50 values of 7.27 and 4.89 mg mL^(-1)respectively,and compound A8 exhibited the best inhibitory activity against Psa with EC50value of 4.87 mg mL^(-1).Pot experiments showed that compound A17 exhibited excellent in vivo antibacterial activities to manage rice bacterial leaf blight and citrus bacterial canker,with protective efficiencies of 52.67 and 79.79%at 200 mgmL^(-1),***,compound A8 showed good control efficiency(84.31%)against kiwifruit bacterial canker at 200 mg mL^(-1).Antibacterial mechanism suggested that these compounds could interfere with the balance of the redox system,damage the cell membrane,and induce the apoptosis of Xoo *** together,our study revealed that tetrahydro-β-carboline derivatives could be a promising candidate model for novel broadspectrum bactericides.

关键词： tetrahydro-β-carboline derivatives antibacterial activity ROS cell apoptosis

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Rapid identification of full-length genome and tracing variations of monkeypox virus in clinical specimens based on mNGS and amplicon sequencing

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Virologica Sinica 2024年第1期39卷 134-143页

作者： Changcheng Wu Ruhan A Sheng Ye Fei Ye Weibang Huo Roujian Lu Yue Tang Jianwei Yang Xuehong Meng Yun Tang Shuang Chen Li Zhao Baoying Huang Zhongxian Zhang Yuda Chen Dongfang Li Wenling Wang Ke-jia Shan Jian Lu Wenjie Tan NHC key laboratory of Biosafety National Institute for Viral Disease Control and PreventionChinese Center for Disease Control and PreventionBeijing100052China Chongqing Municipal key laboratory for High pathogenic Microbes Chongqing Center for Disease Control and PreventionChongqing400042China MGI BGI-ShenzhenShenzhen518083China Thermo Fisher Scientific Beijing100013China School of Public Health Baotou Medical CollegeBaotou014030China BGI PathoGenesis Pharmaceutical Technology Shenzhen518000China State key laboratory of Protein and Plant Gene Research Center for BioinformaticsSchool of Life SciencesPeking UniversityBeijing100871China College of Life Sciences University of Chinese Academy of SciencesBeijing100049China

The monkeypox virus(MPXV)has triggered a current outbreak *** sequencing of MPXV and rapid tracing of genetic variants will benefit disease diagnosis and *** is a significant challenge but necessary to optimize the strategy and application of rapid full-length genome identification and to track variations of MPXV in clinical specimens with low viral loads,as it is one of the DNA viruses with the largest genome and the most AT-biased,and has a significant number of tandem *** we evaluated the performance of metagenomic and amplicon sequencing techniques,and three sequencing platforms in MPXV genome sequencing based on multiple clinical specimens of five mpox cases in Chinese *** rapidly identified the full-length genome of MPXV with the assembly of accurate tandem repeats in multiple clinical *** sequencing enables cost-effective and rapid sequencing of clinical specimens to obtain high-quality MPXV ***-generation sequencing facilitates the assembly of the terminal tandem repeat regions in the monkeypox virus genome and corrects a common misassembly in published ***,several intra-host single nucleotide variations were identified in the first imported mpox *** study offers an evaluation of various strategies aimed at identifying the complete genome of MPXV in clinical *** findings of this study will significantly enhance the surveillance of MPXV.

关键词： Monkeypox virus(MPXV) Metagenomic Next generation sequencing Amplicon Third-generation sequencing

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The infection kinetics and transmission potential of two Guaico Culex viruses in Culex quinquefasciatus mosquitoes

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Virologica Sinica 2024年第2期39卷 228-234页

作者： Ru-Yi Chen Teng Zhao Jing-Jing Guo Feng Zhu Na-Na Zhang Xiao-Feng Li Hai-Tao Liu Fei Wang Yong-Qiang Deng Cheng-Feng Qin College of Bioscience and Bioengineering Jiangxi Agricultural UniversityNanchang330045China State key laboratory of Pathogen and Biosecurity Beijing Institute of Microbiology and EpidemiologyAMMSBeijing100071China School of Life Sciences Southwest Forestry UniversityKunming650224China

Guaico Culex virus(GCXV)is a newly identified segmented Jingmenvirus from Culex *** in Central and South *** genome of GCXV is composed of four or five single-stranded positive RNA ***,the infection kinetics and transmission capability of GCXV in mosquitoes remain *** this study,we used reverse genetics to rescue two GCXVs(4S and 5S)that contained four and five RNA segments,respectively,in C6/36 *** in vitro characterization revealed that the two GCXVs exhibited comparable replication kinetics,protein expression and viral ***,GCXV RNAs were detected in the bodies,salivary glands,midguts and ovaries of Culex quinquefasciatus at 4–10 days after oral *** addition,two GCXVs can colonize *** eggs,resulting in positive rates of 15%–35%for the second gonotrophic *** conclusion,our results demonstrated that GCXVs with four or five RNA segments can be detected in *** eggs during the first and second gonotrophic cycles after oral infection.

关键词： Guaico Culex virus(GCXV) Jingmenvirus Culex quinquefasciatus Vertical transmission

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Chronic social defeat stress‑induced depression reduces BCG efficacy by promoting regulatory T‑cell levels in mice

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Animal Diseases 2024年第2期4卷 115-126页

作者： Rohit Tyagi Xi Chen Atika Dhar Bing Yang Wei Zhou Aikebaier Reheman Yingying Lei Gang Cao National key laboratory of Agricultural microbiology College of Veterinary MedicineHuazhong Agricultural UniversityWuhan 430070China National Institute of immunology New Delhi 110067India College of Animal Science and Technology Tarim UniversityAlar 843300China Bio‑Medical Center Huazhong Agricultural UniversityWuhan 430070China

Despite the initial successes of the Bacillus Calmette-Guerin(BCG)vaccine in children,its efficacy against tuberculosis is highly *** is a lack of understanding about how mental conditions influence BCG ***,we used the chronic social defeat stress(CSDS)model to explore the effects of depression on BCG vaccination *** observed higher lung and spleen bacterial loads and a lower organ index in depressed compared to BCG ***,a relatively lower T cell protective efficacy was observed in both compared to control and BCG mice via a mycobacterium growth inhibition assay(MGIA).Cytokine expression of IL-12p40,IL-1β,IL-17,TNF-αand IFN-γwas reduced,whereas the expression of IL-10 and IL-5 was increased in the spleen of both compared to BCG ***,the proportions of CD4^(+)IFN-γ^(+),CD8^(+)IFN-γ^(+)T lymphocytes and CD4^(+)effector/central memory T cells were reduced in the splenocytes of the depressed BCG *** promotes CD4^(+)regulatory T cells(Treg)and myeloid-derived suppressor cell(MDSC)generation in depressed mice,contributing to the reduced pro-inflammatory immune response upon BCG *** study provides insight into the decreased protective immunity by BCG vaccination attributable to depression in mice.

关键词： BCG Vaccine efficacy Treg Immune suppression Depression

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Biomolecular condensates and disease pathogenesis

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Science China Life Sciences 2024年第9期67卷 1792-1832页

作者： Ke Ruan Ge Bai Yanshan Fang Dan Li Tingting Li Xingguo Liu Boxun Lu Qing Lu Zhou Songyang Shuguo Sun Zheng Wang Xin Zhang Wen Zhou Hong Zhang Neurology Department at Huashan Hospital State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science Institutes of Brain Science School of Life Sciences Fudan University key laboratory for the Genetics of Developmental and Neuropsychiatric Disorders Ministry of Education Bio-X Institutes Shanghai Jiao Tong University State key laboratory of Biocontrol MOE Key Laboratory of Gene Function and Regulation and Guangzhou Key Laboratory of Healthy Aging Research School of Life Sciences Sun Yat-sen Memorial HospitalSun Yat-sen University Department of Human Anatomy Histology and Embryology School of Basic Medicine Tongji Medical College Huazhong University of Science and Technology The Second Affiliated Hospital School of Basic Medical Sciences Institute of Biomedical Innovation Jiangxi Medical College Nanchang University Westlake laboratory of Life Sciences and Biomedicine Department of immunology and microbiology School of Life Sciences Southern University of Science and Technology National laboratory of Biomacromolecules Institute of Biophysics Chinese Academy of Sciences College of Life Sciences University of Chinese Academy of Sciences The First Affiliated Hospital & School of Life Sciences Ministry of Education Key Laboratory for Membrane-less Organelles & Cellular Dynamics Hefei National Research Center for Interdisciplinary Sciences at the Microscale Center for Advanced Interdisciplinary Science and Biomedicine of IHM Division of Life Sciences and Medicine University of Science and Technology of China Nanhu Brain-computer Interface Institute Department of Neurology of Second Affiliated Hospital and School of Brain Science and Brain Medicine Zhejiang University School of Medicine Interdisciplinary Research Center on Biology and Chemistry Shanghai Institute of Organic Chemistry Chinese Academy of Sciences University of Chinese Academy of Sciences Bio-X Institutes Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of

Biomolecular condensates or membraneless organelles(MLOs) formed by liquid-liquid phase separation(LLPS) divide intracellular spaces into discrete compartments for specific functions. Dysregulation of LLPS or aberrant phase transition that disturbs the formation or material states of MLOs is closely correlated with neurodegeneration, tumorigenesis, and many other pathological processes. Herein, we summarize the recent progress in development of methods to monitor phase separation and we discuss the biogenesis and function of MLOs formed through phase separation. We then present emerging proof-of-concept examples regarding the disruption of phase separation homeostasis in a diverse array of clinical conditions including neurodegenerative disorders, hearing loss, cancers, and immunological diseases. Finally, we describe the emerging discovery of chemical modulators of phase separation.

关键词： liquid-liquid phase separation biomolecular condensate membraneless organelle

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Cofitness network connectivity determines a fuzzy essential zone in open bacterial pangenome

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mLife 2024年第2期3卷 277-290页

作者： Pan Zhang Biliang Zhang Yuan-Yuan Ji Jian Jiao Ziding Zhang Chang-Fu Tian State key laboratory of Plant Environmental Resilience and College of Biological SciencesChina Agricultural UniversityBeijingChina MOA key laboratory of Soil microbiology and Rhizobium Research CenterChina Agricultural UniversityBeijingChina Shenzhen Institute of Synthetic Biology Shenzhen Institute of Advanced TechnologyChinese Academy of SciencesShenzhenChina State key laboratory of Livestock and Poultry Biotechnology Breeding and College of Biological SciencesChina Agricultural UniversityBeijingChina

Most in silico evolutionary studies commonly assumed that core genes are essential for cellular function,while accessory genes are dispensable,particularly in nutrient-rich ***,this assumption is seldom tested genetically within the pangenome *** this study,we conducted a robust pangenomic Tn-seq analysis of fitness genes in a nutrient-rich medium for Sinorhizobium strains with a canonical open *** evaluate the robustness of fitness category assignment,Tn-seq data for three independent mutant libraries per strain were analyzed by three methods,which indicates that the Hidden Markov Model(HMM)-based method is most robust to variations between mutant libraries and not sensitive to data size,outperforming the Bayesian and Monte Carlo simulation-based ***,the HMM method was used to classify the fitness *** genes,categorized as essential(ES),advantage(GA),and disadvantage(GD)genes for growth,are enriched in core genes,while nonessential genes(NE)are over-represented in accessory *** ES/GA genes showed a lower fitness effect than core ES/GA *** degrees in the cofitness network decrease in the order of ES,GD,and GA/*** addition to accessory genes,1599 out of 3284 core genes display differential essentiality across test *** the pangenome core,both shared quasi-essential(ES and GA)and strain-dependent fitness genes are enriched in similar functional *** analysis demonstrates a considerable fuzzy essential zone determined by cofitness connectivity degrees in Sinorhizobium pangenome and highlights the power of the cofitness network in understanding the genetic basis of ever-increasing prokaryotic pangenome data.

关键词： cofitnessnetwork pangenome Tn-seq

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The protective effects of fermented vinegar on acute alcohol-induced hepatic and neuro-toxicity by regulating ethanol metabolism and gut microbiota

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Food Science and Human Wellness 2024年

作者： Yuan Meng Yunfan Liu Ting Xia Beibei Geng Yinglei Tian Hailong Cao Jin Yan Xiaoqi Pang Kai Liang Yufeng Yan Min Wang State key laboratory of Food Nutrition and Safety， key laboratory of Industrial Fermentation microbiology， College of Biotechnology， Tianjin University of Science and Technology Department of Gastroenterology and Hepatology， General Hospital， Tianjin Medical University， National key Clinical Specialty， Tianjin Institute of Digestive Diseases， Tianjin key laboratory of Digestive Diseases Shanxi Provincial key laboratory for Vinegar Fermentation Science and Engineering， Shanxi Zilin Vinegar Industry Co.， Ltd.

Alcohol abuse constitutes a significant health hazard， leading to various organ damage， notably the liver and brain. Shanxi aged vinegar (SAV) is one of the famous fermented and functional foods containing a variety of bioactive ingredients with beneficial effects on the human body. This study aimed to explore the potential protective effect of SAV in alleviating acute alcohol intoxication (AAI) in mice. It was found that SAV at 2.5 mg/kg BW effectively ameliorated the decline in behavioral abilities following alcohol consumption， characterized by a shortened sobering period. SAV reduces alcohol-induced liver damage by inhibiting hepatic function enzymes and oxidative stress levels. Additionally， SAV mitigated the overactivation of microglia and the downregulation of neurotransmitter levels (AchE， 5-HT， and DA)， thereby reducing ethanol-induced brain damage. Meanwhile， SAV significantly decreased concentrations of alcohol and acetaldehyde in the blood and increased ADH and ALDH activities in the liver， indicating enhancement of ethanol metabolism. Moreover， we found that some gut microbiota including Verrucomicrobiota， Akkermansia， and Enterococcus were downregulated after SAV treatment in mice with AAI. These bacteria showed a negative correlation with anti-oxidative markers (GSH and CAT) and enzymes related to ethanol metabolism pathways (ADH and ALDH)， and a positive correlation with hepatic function markers (ALT， AST， and MDA)， alcohol metabolites (alcohol and acetaldehyde) and neurotransmitters (AchE， 5-HT， and DA). However， Bacteroidota， norank＿f＿Muribaculaceae， and Alistipes exhibited the opposite direction. These findings suggest that SAV possesses protective effects against hepatic and neuro-toxicity， and could be a potential functional food for AAI prevention.

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Asymmetric reduction of conjugated C=C bonds by immobilized fusion of old yellow enzyme and glucose dehydrogenase

Green Synthesis and Catalysis

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Green Synthesis and Catalysis 2024年第2期5卷 80-87页

作者： Yongxing Li Pengqian Luan Lele Dong Jianqiao Liu Luying Jiang Jing Bai Fufeng Liu Yanjun Jiang School of Chemical Engineering and Technology Hebei University of TechnologyTianjin 300130China College of Food Science and Biology Hebei University of Science&Technology26 Yuxiang StreetYuhua DistrictShijiazhuang 050018China key laboratory of Industrial Fermentation microbiology of Ministry of Education Tianjin Key Laboratory of Industrial MicrobiologyCollege of BiotechnologyTianjin University of Science&TechnologyTianjin 300457China

Asymmetric reduction of the conjugated C=C bonds by the old yellow enzymes(OYEs)presents a promising field in the synthesis of chiral ***,few natural OYEs have been applied in large-scale applications due to the requirement of costly NADPH and low operational ***,a stable and efficient fusion of YqjM from Bacillus subtilis and glucose dehydrogenase(GDH)from Bacillus megaterium was constructed to stereoselectively reduce the conjugated C=C bonds in a self-sufficient continuous *** effects of the enzyme order and different linkers on the fusions were investigated by structural analysis and all-atom molecular dynamics *** best fusion YqjM_G_GDH gave 98% conversion of 100 mmol/L 2-methylcyclopentenone with an excellent ee value(>99%)in 3 h,while the mixture of individual enzymes only obtained 68% conversion after more than 8 *** improved substrate conversion of YqjM_G_GDH fusion was probably attributed to the increased flexibility of each fused enzyme and the shortening of the diffusion distance of NADPH regenerated.A one-pot process was designed to purify and immobilize the fusion on the Ni2t-nitrilotriacetic acid functionalized magnetic mesoporous silica *** resulting immobilized biocatalyst not only catalyzed the asymmetric reduction of various α,β-unsaturated ketones(20 mmol/L)continuously with only 50μmol/L NADPt to initiate the whole process,but also retained more than 82%of the initial activity after seven cycles,serving as a good candidate for the industrial applications.

关键词： Enzyme fusion Old yellowenzymes Asymmetricreduction C=C bond Cofactor regeneration Immobilization

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The OsBZR1-OsSPX1/2 module fine-tunes the growth-immunity trade-off in adaptation to phosphate availability in rice

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Molecular Plant 2024年第2期17卷 258-276页

作者： Yuqing He Yao Zhao Jitao Hu Lanlan Wang Linying Li Xueying Zhang Zhongjing Zhou Lili Chen Hua Wangl Jiaoyu Wang Gaojie Hong State key laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-Products Key Laboratory of Biotechnology in Plant Protection of MOA of China and Zhejiang ProvinceInstitute of Virology and BiotechnologyZhejiang Academy of Agricultural SciencesHangzhou 310021P.R.China key laboratory of Traceability for Agricultural Genetically Modified Organisms Ministry of Agriculture and Rural AffairsHangzhou 310021P.R.China College of Life Sciences Zhejiang Sci-Tech UniversityHangzhou 310018P.R.China State key laboratory for Managing Biotic and Chemical Threats to the Qualty and Safety of Agro-products Zhejang Academy of Agricultural SciencesHangzhou 310021P.R.China State key laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-Products Key Labory of Biotechnology in Plant Protection of MOA of China and Zhejiang ProvinceInstitute of Plant Protection and MicrobiologyZhejiang Academy of Agricultural SciencesHangzhou 310021P.R.China

The growth-promoting hormones brassinosteroids(BRs)and their key signaling component BZR1 play a vital role in balancing normal growth and defense ***,we discovered that BRs and OsBZR1 up-regulated sakuranetin accumulation and conferred basal defense against Magnaporthe oryzae infection under normal *** shortages,including phosphate(Pi)deficiency,potentially disrupt this growth-defense ***1 and OsSPX2 have been reported to sense Pi concentration and interact with the Pi signal mediator OsPHR2,thus regulating Pi starvation *** this study,we discovered that OsSPX1/2 interacts with OsBZR1 in both Pi-sufficient and Pi-deficient conditions,inhibit-ing BR-responsive *** Pi is sufficient,OsSPX1/2 is captured by OsPHR2,enabling most of OsBzR1 to promote plant growth and maintain basal *** response to Pi starvation,more OsSPX1/2 is released from OsPHR2 to inhibit OsBZR1 activity,resulting in slower ***,our study reveals that the OsBZR1-SPX1/2 module balances the plant growth-immunity trade-off in *** Y.,Zhao Y.,Hu J.,Wang L.,Li L.,Zhang X.,Zhou Z.,Chen L.,Wang H.,Wang J.,and Hong G.(2024).The OsBZR1-OsSPX1/2 module fine-tunes the growth-immunity trade-off in adaptation to phosphate availability in esponse to Pi availability.

关键词： immunity maintain adaptation

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