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

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Acta Pharmaceutica Sinica B 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

Design and performance of air flow-assisted ionization imaging mass spectrometry system

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Chinese Chemical Letters 2014年第5期25卷 687-692页

作者： Fei Tang Yi Chen Jiu-Ming He Zhi-Gang Luo Zeper Abliz Xiao-Hao Wang State Key laboratory of Precision Measurement Technology and Instruments Department of Precision InstrumentTsinghua University State Key laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical College

The imaging mass spectrometry（IMS） technology has experienced a rapid development in recent years.A new IMS technology which is based on air flow assisted ionization（AFAI） was *** allows for the convenient pretreatment of the samples and can image a large area of sample in a single measurement with high *** AFAI in DESI mode was used as the ion source in this *** new IMS method is named *** adoption of assisted air flow makes the sample pretreatment easy and *** optimization of the distance between the ion transport tube and MS orifice increases the sensitivity of the *** data processing,a program based on MATLAB with the function of numerical analysis was developed.A theoretical imaging resolution of a few hundred microns can be *** composite AFAI-IMS images of different target analytes were imaged with high sensitivity.A typical AFAI-IMS image of the whole-body section of a rat was obtained in a single analytical *** ability to image a large area for relevant samples in a single measurement with high sensitivity and repeatability is a significant *** method has enormous potentials in the MS imaging of large and complicated samples.

关键词： Imaging mass spectrometry Air flow assisted ionization imaging mass spectrometry Whole-body imaging Large and complicated sample imaging

Pharmacokinetics of H002, a novel S1PR_1 modulator, and its metabolites in rat blood using liquid chromatography–tandem mass spectrometry

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Acta Pharmaceutica Sinica B 2016年第6期6卷 576-583页

作者： Jiaqi Mi Manman Zhao Shu Yang Shuang Yang Jing Jin Xiaojian Wang Qiong Xiao Jinping Hu Yan Li Department of Drug Metabolism Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD StudyKey Laboratory of Active Substances Discovery and Drug Ability Evaluation State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia Medica Chinese Academy of Medical Sciences & Peking Union Medical College

A rapid and sensitive liquid chromatography–tandem mass spectrometry(LC–MS/MS) method was developed and validated for the simultaneous determination of H002 and its phosphorylated metabolite, H002-P and hydroxylated metabolite H002-M, in rat blood. H001, an analogue of H002, was used as the internal *** samples were prepared by simple protein precipitation. The analytes and internal standard were separated on a Zorbax SB-C18 column with a gradient mobile phase consisting of methanol and water containing 0.1% formic acid at a flow rate of 0.2 mL /min with an operating temperature of 20 1C. The detection was performed on a triple quadrupole tandem mass spectrometer with positive electrospray ionization in multiple-reaction monitoring *** detection responses were obtained from 0.2–100 ng/mL for H002 and H002-M, while 0.5–100 ng/mL for H002-P. The intra- and inter-day precision(RSD%) was within 11.76%, with the accuracy(RE%) ranging from –9.84% to 9.12%. The analytes were shown to be stable during sample storage, preparation and analytic *** method was applied to determine the pharmacokinetics of H002 in rats, and a preliminary study showed that the pharmacokinetics of H002 correlated with its biological effect on peripheral blood lymphocytes.

关键词： S1P receptor S1PR1 modulator Sphingosine-1-phosphate S1P analogue Metabolite LC–MS/MS Pharmacokinetics Periphery blood lymphocyte

Discovering metabolic vulnerability using spatially resolved metabolomics for antitumor small molecule-drug conjugates development as a precise cancer therapy strategy

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Journal of Pharmaceutical Analysis 2023年第7期13卷 776-787页

作者： Xiangyi Wang Jin Zhang Kailu Zheng Qianqian Du Guocai Wang Jianpeng Huang Yanhe Zhou Yan Li Hongtao Jin Jiuming He State Key laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing100050China NMPA Key laboratory of Safety Research and Evaluation of Innovative Drug Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing100050China Beijing Key laboratory of New Drug Mechanisms and Pharmacological Evaluation Study Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing100050China New Drug Safety Evaluation Center Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing100050China

Against tumor-dependent metabolic vulnerability is an attractive strategy for tumor-targeted ***,metabolic inhibitors are limited by the drug resistance of cancerous cells due to their metabolic plasticity and ***,choline metabolism was discovered by spatially resolved metabolomics analysis as metabolic vulnerability which is highly active in different cancer types,and a choline-modified strategy for small molecule-drug conjugates(SMDCs)design was developed to fool tumor cells into indiscriminately taking in choline-modified chemotherapy drugs for targeted cancer therapy,instead of directly inhibiting choline *** a proof-of-concept,choline-modified SMDCs were designed,screened,and investigated for their druggability in vitro and in *** strategy improved tumor targeting,preserved tumor inhibition and reduced toxicity of paclitaxel,through targeted drug delivery to tumor by highly expressed choline transporters,and site-specific release by *** study expands the strategy of targeting metabolic vulnerability and provides new ideas of developing SMDCs for precise cancer therapy.

关键词： mass spectrometry imaging Spatially resolved metabolomics Small molecule-drug conjugate Tumor metabolism Targeted tumor therapy

Rearrangement of Actin Cytoskeleton by Zika Virus Infection Facilitates Blood–Testis Barrier Hyperpermeability

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Virologica Sinica 2021年第4期36卷 692-705页

作者： Yiwen Nie Lixia Hui Moujian Guo Wei Yang Rui Huang Junsen Chen Xinyue Wen Meng Zhao Ying Wu State Key laboratory of Virology School of Basic Medical SciencesWuhan UniversityWuhan 430072China Hubei Province Key laboratory of Allergy and Immunology Wuhan 430071China

In recent years,various serious diseases caused by Zika virus(ZIKV)have made it impossible to be *** existence of ZIKV in semen and sexually transmission of ZIKV suggested that it can break the blood–testis barrier(BTB),or Sertoli cell barrier(SCB).However,little is known about the underlying *** this study,interaction between actin,an important component of the SCB,and ZIKV envelope(E)protein domainⅢ(EDⅢ)was inferred from coimmunoprecipitation(Co-IP)liquid chromatography–tandem mass spectrometry(LC–MS/MS)*** microscopy confirmed the role of actin filaments(F-actin)in ZIKV infection,during which part of the stress fibers,the bundles that constituted by paralleled actin filaments,were disrupted and presented in the cell *** of E and reorganized actin filaments in the cell periphery of transfected Sertoli cells suggests a participation of ZIKV E protein in ZIKV-induced F-actin *** of F-actin by cytochalasin D(CytoD)or Jasplakinolide(Jas)enhanced the infection of *** importantly,the transepithelial electrical resistance(TEER)of an in vitro mouse SCB(mSCB)model declined with the progression of ZIKV infection or overexpression of E ***-IP and confocal microscopy analyses revealed that the interaction between F-actin and tight junction protein ZO-1 was reduced after ZIKV infection or E protein overexpression,highlighting the role of E protein in ZIKV-induced disruption of the *** conclude that the interaction between ZIKV E and F-actin leads to the reorganization of F-actin network,thereby compromising BTB integrity.

关键词： Zika virus(ZIKV) Envelope protein Actin filaments Sertoli cell barrier(SCB) Blood-testis barrier(BTB)

High-throughput screening for amyloid-β binding natural small-molecules based on the combinational use of biolayer interferometry and UHPLC−DAD-Q/TOF-MS/MS

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Acta Pharmaceutica Sinica B 2022年第4期12卷 1723-1739页

作者： Minsong Guo Fengdan Zhu Wenqiao Qiu Gan Qiao Betty Yuen-Kwan Law Lu Yu Jianming Wu Yong Tang Chonglin Yu Dalian Qin Xiaogang Zhou Anguo Wu Sichuan Key medical laboratory of New Drug Discovery and Druggability Evaluation Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia MedicaSchool of PharmacyEducation Ministry Key Laboratory of Medical ElectrophysiologySouthwest Medical UniversityLuzhou 646000China State Key laboratory of Quality Research in Chinese Medicine Macao University of Science and TechnologyTaipaMacao 999078China Department of Neurosurgery Sichuan Provincial People’s Hospital University of Electronic Science and Technology of ChinaChengdu 610000China

Discovery of drugs rapidly and effectively is an important aspect for Alzheimer's disease(AD).In this study,a novel high-throughput screening(HTS)method aims at screening the small-molecules with amyloid-β(Aβ)binding affinity from natural medicines,based on the combinational use of biolayer interferometry(BLI)and ultra-high-performance liquid chromatography coupled with diode-array detector and quadrupole/time-of-flight tandem mass spectrometry(UHPLC−DAD-Q/TOF-MS/MS)has been firstly ***,the components in natural medicines disassociated from biotinylated Aβwere collected to analyze their potential Aβbinding affinity by UHPLC−DAD-Q/TOF-MS/***,baicalein was confirmed to exhibit the highest binding affinity with Aβin Scutellaria ***,polyporenic acid C(PPAC),dehydrotumulosic acid(DTA),and tumulosic acid(TA)in Kai-Xin-San(KXS)were also identified as potent Aβ*** bioactivity validations indicated that these compounds could inhibit Aβfibrillation,improve the viability in Aβ-induced PC-12 cells,and decrease the Aβcontent and improve the behavioral ability in Caenorhabditis *** molecular docking results confirmed that PPAC,DTA,and TA possessed good binding properties with Aβ.Collectively,the present study has provided a novel and effective HTS method for the identification of natural inhibitors on Aβfibrillation,which may accelerate the process on anti-AD drugs discovery and development.

关键词： Alzheimer’s disease High-throughput screening Biolayer interferometry UHPLCDAD-Q/TOFMS/MS Kai-Xin-San

Ribotrap Analysis of Proteins Associated with FHL3 3'Untranslated Region in Glioma Cells

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Chinese medical Sciences Journal 2014年第2期29卷 78-84页

作者： Wei Han Qing Xia Bin Yin Xiao-zhong Peng State Key laboratory of medical Molecular Biology Department of Biochemistry and Molecular Biology Institute of Basic Medical Sciences Chinese Academy of Medical Sciences & Peking Union Medical College Beijing 100005 China State Key laboratory of Proteomics Institute of Basic Medical Sciences National Center of Biomedical Analysis Beijing 100850 China

Objective To screen the proteins associated with four-and-a-half LIM domains 3(FHL3) 3' untranslated region(3'UTR) in glioma cells. Methods Western blot was adopted to detect the regulatory effect of poly(C)-binding protein 2(PCBP2) on FHL3. Biotin pull-down and sliver staining were employed to screen and verify the candidate binding proteins of FHL3 3'UTR. Then liquid chromatography-tandem mass spectrometry(LC-MS/MS) and molecule annotation system were used to identify and analyze the candidate binding proteins. Immunoprecipitation was conducted to study the interaction between PCBP2 and polypyrimidine tract-binding protein 1(PTBP1), a binding protein identified by LC-MS/MS. Results PCBP2 could bind to FHL3 mRNA 3'UTR-A and inhibited the expression of FHL3 in T98 G glioms cells. 22 candidate binding proteins were identified. Among them, there were 11 RNA binding proteins, including PCBP2. PTBP1 associated with FHL3 mRNA 3'UTR and interacted with PCBP2 protein. Conclusion PCBP2 and PTBP1 can both associate with FHL3 mRNA 3'UTR through forming a protein complex.

关键词： FHL3 3'untranslated region poly(C)-binding protein 2 polypyrimidine tract-binding protein 1 liquid chromatography-tandem mass spectrometry

Exploring pathogenesis of primary biliary cholangitis by proteomics: A pilot study

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World Journal of Gastroenterology 2017年第48期23卷 8489-8499页

作者： Chui-Wen Deng Li Wang Yun-Yun Fei Chao-Jun Hu Yun-Jiao Yang Lin-Yi Peng Xiao-Feng Zeng Feng-Chun Zhang Yong-Zhe Li Department of Rheumatology and Clinical Immunology Peking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical College Key laboratory of Rheumatology and Clinical Immunology Ministry of Education

AIM To explore the pathogenesis of primary biliary cholangitis(PBC) by identifying candidate autoantibodies in serum samples by proteomics and *** Nine antimitochondrial antibody(AMA)-positive PBC patients and nine age-and sex-matched AMA-negative PBC patients were recruited. Antigen enrichment technology was applied to capture autoantigens of human intrahepatic biliary epithelial cells(Hi BECs) that are recognized by autoantibodies from the sera of PBC patients. Candidate autoantigens were identified by label-free mass spectrometry. Bioinformatics analysis with Max Quant software(version 1.***.2.8),DAVID platform,and Cytoscape v.3.0 allowed illustration of pathways potentially involved in the pathogenesis of *** In total,1081 candidate autoantigen proteins were identified from the PBC patient pool. Among them,371 were determined to be significantly differentially expressed between AMA-positive and-negative PBC patients(P < 0.05). Fisher's exact test was performed for enrichment analysis of Gene Ontology protein annotations(biological processes,cellular components,and molecular functions) and the Kyoto Encyclopedia of Genes and Genomes pathways. Significantly different protein categories were revealed between AMA-positive and-negative PBC patients. As expected,autoantigens related to mitochondria were highly enriched in AMApositive PBC patients. However,lower levels of AMA were also detected in AMA-negative PBC patients. In addition,autoantigens of AMA-negative PBC patients were mainly involved in B-cell activation,recognition of phagocytosis,and complement *** AMA-negative PBC individuals may not exist,but rather,those patients exhibit pathogenesis pathways different from those of AMA-positive PBC. Comprehensive research is needed to confirm these observations.

关键词： Anti-mitochondrial antibody Bioinformatics Pathogenesis Primary biliary cholangitis Proteomics

Herb-drug interaction in the protective effect of Alpinia officinarum against gastric injury induced by indomethacin based on pharmacokinetic, tissue distribution and excretion studies in rats

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Journal of Pharmaceutical Analysis 2021年第2期11卷 200-209页

作者： Xuguang Zhang Zhenrui Xie Xun Chen Junqiang Qiu Yinfeng Tan Xiaoliang Li Hailong Li Junqing Zhang Key laboratory of Tropical Translation Medicine of Ministry of Education Hainan Provincial Key Laboratory for Research and Development of Tropical HerbsSchool of PharmacyHainan Medical UniversityHaikou571199China

Alpinia officinarum Hance of the Chinese traditional herb for the treatment of emesis, abdominal pain and diarrhea has been used to counteract gastric disease induced by indomethacin in rats without obvious side effects. However, the role of herb-drug interaction between indomethacin and A. officinarum based on pharmacokinetic, tissue distribution and excretion still remains unknown. In this study, an ultra-fast liquid-tandem mass spectrometry(UFLC-MS/MS) method was developed for simultaneous determination of indomethacin and its three metabolites, O-desmethylindomethacin(ODI), deschlorobenzoylindomethacin(NDI) and indomethacin acyl-b-D-glucuronide(IDAbG) by oral administration of indomethacin solution with and without the ethanolic extract of A. officinarum and applied to comparative pharmacokinetic, tissue distribution and excretion studies. Our results clarified that oral administration of A. officinarum produced significant alterations in the pharmacokinetic parameters of indomethacin. And the pharmacokinetic interaction between indomethacin and A. officinarum reduced the systemic exposure of indomethacin and increased its elimination. Tissue distribution results demonstrated that co-administration of A. Officinarum could not reduce the accumulation of indomethacin in the target tissue of the stomach, but could accelerate the excretions of indomethacin and its three metabolites including ODI, NDI and IDAb G in the bile and feces of rats in the excretion ***, A. Officinarum might have a gastrointestinal protective effect through the interaction role with indomethacin based on the pharmacokinetics and excretion in rats.

关键词： Alpinia officinarum Hance Indomethacin Herb-drug interaction Pharmacokinetics Tissue distribution Excretion