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Inferring mycobacterium tuberculosis Drug Resistance and Transmission using Whole-genome Sequencing in a High TB-burden Setting in China

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Biomedical and Environmental Sciences 2024年第2期37卷 157-169页

作者： FAN Yu Feng LIU Dong Xin CHEN Yi Wang OU Xi Chao MAO Qi Zhi YANG Ting Ting WANG Xi Jiang HE Wen Cong ZHAO Bing LIU Zhen Jiang ABULIMITI Maiweilanjiang AIHEMUTI Maimaitiaili GAO Qian ZHAO Yan Lin Key Laboratory of Medical Molecular Virology(MOE/NHC/CAMS) School of Basic Medical SciencesShanghai Medical CollegeFudan UniversityShanghai 200032China National tuberculosis Reference Laboratory Chinese Center for Disease Control and PreventionBeijing 102206China Hangzhou Red Cross Hospital Hangzhou 310005ZhejiangChina Xinjiang Uygur Autonomous Region Center for Disease Control and Prevention Urumqi 830026XinjiangChina tuberculosis Dispensary of Kashgar Prefecture Kashgar 844099XinjiangChina

Objective China is among the 30 countries with a high burden of tuberculosis(TB)worldwide,and TB remains a public health *** Prefecture in the southern Xinjiang Autonomous Region is considered as one of the highest TB burden regions in ***,molecular epidemiological studies of Kashgar are *** A population-based retrospective study was conducted using whole-genome sequencing(WGS)to determine the characteristics of drug resistance and the transmission *** A total of 1,668 isolates collected in 2020 were classified into lineages 2(46.0%),3(27.5%),and 4(26.5%).The drug resistance rates revealed by WGS showed that the top three drugs in terms of the resistance rate were isoniazid(7.4%,124/1,668),streptomycin(6.0%,100/1,668),and rifampicin(3.3%,55/1,668).The rate of rifampicin resistance was 1.8%(23/1,290)in the new cases and 9.4%(32/340)in the previously treated *** resistance mutations were detected more frequently in lineage 2 strains than in lineage 3 or 4 strains,respectively:18.6%vs.8.7 or 9%,Ptuberculosis(DR-TB),78.4%(171/218)were attributed to the transmission of DR-TB *** Our results suggest that drug-resistant strains are more transmissible than susceptible strains and that transmission is the major driving force of the current DR-TB epidemic in Kashgar.

关键词： mycobacterium tuberculosis Whole-genome sequencing(WGS) Transmission Drug resistance Xinjiang

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Discovering peptides and computational investigations of a multiepitope vaccine target mycobacterium tuberculosis

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Synthetic and Systems Biotechnology 2024年第3期9卷 391-405页

作者： Truc Ly Nguyen Heebal Kim Department of Agricultural Biotechnology and Research Institute of Agriculture and Life Sciences Seoul National UniversitySeoul08826Republic of Korea Interdisciplinary Program in Bioinformatics Seoul National UniversitySeoul08826Republic of Korea eGnome Inc.Seoul05836Republic of Korea

mycobacterium tuberculosis(MTB)is the causative agent of tuberculosis(TB),a prevalent airborne infectious *** the availability of the Bacille Calmette-Guerin vaccine,its global efficacy remains modest,and tuberculosis persists as a significant global public health *** this challenge and advancing towards the End MTB Strategy,we developed a multiepitope vaccine(MEV)based on immunoinformatics and compu-tational *** screening of MBT protein identified immune-dominant epitopes based on Major Histocompatibility Complex(MHC)allele binding,immunogenicity,antigenicity,allergenicity,toxicity,and cytokine *** epitopes were integrated into an MEV construct with adjuvant and linkers,forming a fully immunogenic vaccine *** analyses encompassed the evaluation of immunological and physicochemical properties,determination of tertiary structure,molecular docking with Toll-Like Receptors(TLR),molecular dynamics(MD)simulations for all atoms,and immune *** MEV comprises 534 amino acids,featuring 6 cytotoxic T lymphocyte,8 helper T lymphocyte,and 7 linear B lymphocyte epitopes,demonstrating high antigenicity and ***,molecular docking studies and triplicate MD simulations revealed enhanced interactions and stability of MEV with the TLR4 complex compared to *** addition,the immune simulation indicated the capacity to effectively induce elevated levels of an-tibodies and cytokines,emphasizing the vaccine’s robust immunogenic *** study presents a promising MEV against TB,exhibiting favorable immunological and physicochemical *** findings provide theoretical support for TB vaccine *** study aligns with the global initiative of the End MTB Strategy,emphasizing its potential impact on addressing persistent challenges in TB control.

关键词： mycobacterium tuberculosis tuberculosis Multiepitope vaccine Docking molecular Molecular dynamics simulation Immune simulation

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Early Prosthetic Valve Endocarditis with mycobacterium tuberculosis after Mitral Valve Replacement: A Case Report

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World Journal of Cardiovascular Surgery 2024年第3期14卷 33-40页

作者： Papa Amath Diagne Mory Camara Papa Ousmane Ba Momar Sokhna Diop Moussa Samba Abdou Lahad Mbengue Jean Claude Ndiogou Dione Myriam Bizrane Marième Soda Mbaye Moussa Seck Diop Toudiani Malam Kaka Papa Salmane Ba Papa Adama Dieng Amadou Gabriel Ciss Assane Ndiaye Cardiovascular and Thoracic Surgery Department FANN National University Hospital Dakar Senegal

Background: Tuberculous endocarditis is a rare but serious complication of heart valve replacement surgery. We report the case of a 24-year-old patient, who presented with tuberculous endocarditis after mechanical mitral valve replacement, with a favorable clinical course following anti-tuberculosis treatment. Case Presentation: We report a 24-year-old male patient, admitted to the cardiac surgery department of the Fann Hospital (Dakar, Senegal), for the management of severe mixed (rheumatic and endocarditic) mitral insufficiency with associated tricuspid insufficiency. He had a history of recurrent angina and polyarthralgia in childhood, was hospitalized several times for refractory global cardiac decompensation, and for a suspected infective endocarditis a month before his admission. On admission, the clinical examination revealed signs suggestive of mitral and tricuspid insufficiency. Transthoracic echocardiography revealed severe post-endocarditic mitral insufficiency with A3 amputation, highly mobile 15 mm vegetations on the free edge of the large valve, moderate tricuspid insufficiency, and severe pulmonary artery hypertension. Mechanical mitral valve replacement and tricuspid valve annuloplasty using autologous pericardial strip were performed via median sternotomy. After ten days, the patient presented with global cardiac decompensation associated with a clinico-biological infectious syndrome, and tans-oesophageal echography revealed an abscess at the sinotubular junction, communicating with the aorta. A thoraco-abdomino-pelvic CT scan was done, which revealed a bilateral alveolar-interstitial syndrome with mediastinal lymphadenopathy. Anti-tuberculosis treatment with RHZE was initiated for 06 months. The clinical course was favorable. Conclusion: Tuberculous endocarditis in prostheses is a serious complication of heart valve replacement surgery, which may evolve favorably under medical treatment.

关键词： Tuberculous Endocarditis Prosthetic Valve Endocarditis mycobacterium tuberculosis

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mycobacterium tuberculosis Mce2E suppresses the macrophage innate immune response and promotes epithelial cell proliferation

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Cellular & Molecular Immunology 2019年第4期16卷 380-391页

作者： Lihua Qiang Jing Wang Yong Zhang Pupu Ge Qiyao Chai Bingxi Li Yi Shi Lingqiang Zhang George Fu Gao Cui Hua Liu CAS Key Laboratory of Pathogenic Microbiology and Immunology Institute of Microbiology Chinese Academy of Sciences100101 BeijingChina Institute of Health Sciences Anhui University230601 Hefei China Savaid Medical School University of Chinese Academy of Sciences 101408 Beijing China State Key Laboratory of Proteomics Beijing Proteome Research CenterNational Center of Protein Sciences BeijingBeijing Institute of Lifeomics100850 Beijing China

The intracellular pathogen mycobacterium tuberculosis(Mtb)can survive in the host and cause disease by interfering with a variety of cellular *** mammalian cell entry 2(mce2)operon of Mtb has been shown to contribute to tuberculosis ***,little is known about the regulatory roles of Mtb Mce2 family proteins towards host cellular *** we show that the Mce2 family protein Mce2E suppressed the macrophage innate immune response and promoted epithelial cell ***2E inhibited activation of the extracellular signal-regulated kinase(ERK)and Jun N-terminal kinase(JNK)mitogen-activated protein kinase(MAPK)signaling pathways in a non-canonical D motif(a MAPK-docking motif)-dependent manner,leading to reduced expression of TNF and IL-6 in ***,Mce2E promoted proliferation of human lung epithelium-derived lung adenoma A549 cells by inhibiting K48-linked polyubiquitination of eEF1A1 in aβstrand region-dependent *** summary,Mce2E is a novel multifunctional Mtb virulence factor that regulates host cellular functions in a niche-dependent *** data suggest a potential novel target for TB therapy.

关键词： mycobacterium tuberculosis Mce2E innate immune response cell proliferation

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mycobacterium tuberculosis bacteremia in a human immunodeficiency virus-negative patient with liver cirrhosis:A case report

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World Journal of Clinical Cases 2022年第10期10卷 3284-3290页

作者： Zhe-Zhe Lin Dan Chen Sai Liu Jian-Hua Yu Shou-Rong Liu Ming-Li Zhu Department of Open Laboratory Medicine Hangzhou Xixi Hospital Affiliated to Zhejiang Chinese Medical UniversityHangzhou 310000Zhejiang ProvinceChina Department of Infectious Diseases Hangzhou Xixi Hospital Affiliated to Zhejiang Chinese Medical UniversityHangzhou 310000Zhejiang ProvinceChina Department of Hepatology Hangzhou Xixi Hospital Affiliated to Zhejiang Chinese Medical UniversityHangzhou 310000Zhejiang ProvinceChina

BACKGROUND With the increasing prevalence of human immunodeficiency virus(HIV),the incidence of mycobacterium tuberculosis(***)bacteremia has also *** a common affliction of acquired immunodeficiency syndrome patients,*** infection is associated in these patients with severe sepsis and high *** contrast,*** bacteremia is rarely seen in HIVnegative patients,and *** has never been reported from the blood of patients with liver *** SUMMARY We evaluated a 55-year-old Chinese male patient who had been admitted to the hospital with abdominal distension of unknown cause of one-week duration,accompanied by diarrhea,shortness of breath,and occasional *** on these indicators of abnormal inflammation and fever,we suspected the presence of an *** evidence of microbial infection was not found in routine clinical tests and the patient did not show typical clinical symptoms of infection with ***,next-generation sequencing of blood samples nevertheless demonstrated the presence of ***,which was subsequently isolated from blood samples grown in conventional Bac T/ALERT FA blood culture *** Our findings demonstrate that HIV-negative liver cirrhosis patients can also be infected with ***.

关键词： mycobacterium tuberculosis Bacteremia Human immunodeficiency virus Liver cirrhosis High-throughput nucleotide sequencing Case report

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Mutation Characteristics of inhA and katG Genes in Isoniazid-Resistant mycobacterium tuberculosis Patients in Xinjiang

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Journal of Clinical and Nursing Research 2024年第1期8卷 140-145页

作者： Shu-Tao Li Wen-Long Guan He Yang The Eighth Affiliated Hospital of Xinjiang Medical University Urumqi 830000Xinjiang Uyghur Autonomous RegionChina

Objective:To analyze the mutation characteristics of inhA and katG genes in isoniazid-resistant mycobacterium tuberculosis in ***:The katG and inhA in 148 strains of isoniazid-resistant mycobacterium tuberculosis were amplified through fluorescence quantitative PCR,and the amplified products were sequenced and ***:The inhA gene mutation rate of 148 strains of isoniazid-resistant mycobacterium tuberculosis was 13.51%(20/148),among which the inhA gene mutation rate among patients of Han,Uygur,and Kazakh ethnicity were 15.87%,13.21%,and 17.65%,*** was no significant difference in the inhA mutation rate among nationalities(c^(2)=2.897,P>0.05).The mutation rate of the katG gene was 84.46%(125/148),among which the mutation rates of patients of Han,Uyghur,and Kazak ethnicities were 82.54%,84.91%,and 76.47%,*** Hui and other ethnic groups were all affected by the katG gene *** was no significant difference in the mutation rate of the katG gene among different ethnicities(c^(2)=3.772,P>0.05).The mutation rates of the inhA gene in southern Xinjiang,northern Xinjiang,and other provinces were 18.60%,9.28%,and 37.50%,*** mutation rates of the inhA gene in different regions were statistically different(c^(2)=6.381,P0.05)and between southern Xinjiang and other provinces(c^(2)=1.424,P>0.05).However,the mutation rate of the inhA gene in patients from other provinces was higher than that in northern Xinjiang(c^(2)=5.539,P0.05).Conclusion:katG gene mutation was predominant in isoniazid-resistant tuberculosis patients in X

关键词： mycobacterium tuberculosis Drug resistance Isoniazid Gene mutation

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Structure analysis of the extracellular domain reveals disulfide bond forming-protein properties of mycobacterium tuberculosis Rv2969c

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Protein & Cell 2013年第8期4卷 628-640页

作者： Lu Wang Jun Li Xiangxi Wang Wu Liu Xuejun C.Zhang Xuemei Li Zihe Rao National Laboratory of Biomacromolecules Institute of BiophysicsChinese Academy of SciencesBeijing 100101China University of Chinese Academy of Sciences BeijingChina Tianjin Key Laboratory of Protein Science College of Life SciencesNankai UniversityTianjin 300071China

Disulfide bond-forming(Dsb)protein is a bacterial periplasmic protein that is essential for the correct folding and disulfide bond formation of secreted or cell wallassociated *** introduces disulfi de bonds into folding proteins,and is re-oxidized through interaction with its redox partner *** tuberculosis,a Gram-positive bacterium,expresses a DsbA-like protein(Rv2969c),an extracellular protein that has its Nterminus anchored in the cell *** Rv2969c is an essential gene,crucial for disulfi de bond formation,research of DsbA may provide a target of a new class of anti-bacterial drugs for treatment of *** *** the present work,the crystal structures of the extracellular region of Rv2969c(Mtb DsbA)were determined in both its reduced and oxidized *** overall structure of Mtb DsbA can be divided into two domains:a classical thioredoxin-like domain with a typical CXXC active site,and anα-helical *** largely resembles its Escherichia coli homologue EcDsbA,however,it possesses a truncated binding groove;in addition,its active site is surrounded by an acidic,rather than hydrophobic *** our oxidoreductase activity assay,Mtb DsbA exhibited a different substrate specifi city when compared to ***,structural analysis revealed a second disulfi de bond in Mtb DsbA,which is rare in the previously reported DsbA structures,and is assumed to contribute to the overall stability of Mtb *** investigate the disulphide formation pathway in ***,we modeled Mtb Vitamin K epoxide reductase(Mtb VKOR),a binding partner of Mtb DsbA,to Mtb DsbA.

关键词： mycobacterium tuberculosis disulfi de bond forming protein X-ray crystallography

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Molecular basis for the inhibition of β-hydroxyacyI-ACP dehydratase HadAB complex from mycobacterium tuberculosis by flavonoid inhibitors

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Protein & Cell 2015年第7期6卷 504-517页

作者： Yu Dong Xiaodi Qiu Neil Shaw Yueyang Xu Yuna Sun Xuemei Li Jun Li Zihe Rao National Laboratory of Biomacromolecules Institute of Biophysics Chinese Academy of Sciences Beijing 100101 China University of Chinese Academy of Sciences Beijing 100049China Structure Biology Laboratory Tsinghua University Beijing 100084 China Tianjin Key Laboratory of Protein Science College of'Life Sciences Nankai University Tianjin 300071 China

Dehydration is one of the key steps in the biosynthesis of mycolic acids and is vital to the growth of Mycobac- terium tuberculosis （Mtb）. Consequently, stalling dehy-dration cures tuberculosis （TB）. Clinically used anti-TB drugs like thiacetazone （TAC） and isoxyl （ISO） as well as flavonoids inhibit the enzyme activity of the β-hydroxy- acyI-ACP dehydratase HadAB complex. How this inhi- bition is exerted, has remained an enigma for years. Here, we describe the first crystal structures of the MtbHadAB complex bound with flavonoid inhibitor butein, 2＇,4,4＇-trihydroxychalcone or fisetin. Despite sharing no sequence identity from Blast, HadA and HadB adopt a very similar hotdog fold. HadA forms a tight dimer with HadB in which the proteins are sitting side-by-side, but are oriented anti-parallel. While HadB contributes the catalytically critical His-Asp dyad, HadA binds the fatty acid substrate in a long channel. The atypical double hotdog fold with a single active site formed by MtbHadAB gives rise to a long, narrow cavity that vertically traverses the fatty acid binding channel. At the base of this cavity lies Cys61, which upon muta- tion to Ser confers drug-resistance in TB patients. We show that inhibitors bind in this cavity and protrude into the substrate binding channel. Thus, inhibitors of MtbHadAB exert their effect by occluding substrate from the active site, The unveiling of this mechanism of inhibition paves the way for accelerating development of next generation of anti-TB drugs,

关键词： mycobacterium tuberculosis hotdog fold,mycolic acid dehydratase flavonoid thiacetazone isoxyl

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Overcoming mycobacterium tuberculosis through small molecule inhibitors to break down cell wall synthesis

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Acta Pharmaceutica Sinica B 2022年第8期12卷 3201-3214页

作者： Wenbin Kuang Haolin Zhang Xiao Wang Peng Yang State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization China Pharmaceutical UniversityNanjing 210009China Department of Medicinal Chemistry School of PharmacyChina Pharmaceutical UniversityNanjing 210009China

mycobacterium tuberculosis(MTB) utilizes multiple mechanisms to obtain antibiotic resistance during the treatment of infections. In addition, the biofilms, secreted by MTB, can further protect the latter from the contact with drug molecules and immune cells. These self-defending mechanisms lay a formidable challenge to develop effective therapeutic agents against chronic and recurring antibiotictolerant MTB infections. Although several inexpensive and effective drugs(isoniazid, rifampicin, pyrazinamide and ethambutol) have been discovered for the treatment regimen, MTB continues to cause considerable morbidity and mortality worldwide. Antibiotic resistance and tolerance remain major global issues, and innovative therapeutic strategies are urgently needed to address the challenges associated with pathogenic bacteria. Gratifyingly, the cell wall synthesis of tubercle bacilli requires the participation of many enzymes which exclusively exist in prokaryotic organisms. These enzymes, absent in human hepatocytes, are recognized as promising targets to develop anti-tuberculosis drug. In this paper, we discussed the critical roles of potential drug targets in regulating cell wall synthesis of MTB. And also, we systematically reviewed the advanced development of novel bioactive compounds or drug leads for inhibition of cell wall synthesis, including their discovery, chemical modification, in vitro and in vivo evaluation.

关键词： mycobacterium tuberculosis Small molecule inhibitor Cell wall synthesis Antibiotic resistance

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Cryo-EM structures for the mycobacterium tuberculosis iron-loaded siderophore transporter IrtAB

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Protein & Cell 2023年第6期14卷 448-458页

作者： Shan Sun Yan Gao Xiaolin Yang Xiuna Yang Tianyu Hu Jingxi Liang Zhiqi Xiong Yuting Ran Pengxuan Ren Fang Bai Luke WGuddat Haitao Yang Zihe Rao Bing Zhang Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology ShanghaiTech UniversityShanghai 201210China State Key Laboratory of Medicinal Chemical Biology Nankai UniversityTianjin 300353China Laboratory of Structural Biology Tsinghua UniversityBeijing 100084China National Laboratory of Biomacromolecules CAS Center for Excellence in BiomacromoleculesInstitute of BiophysicsChinese Academy of SciencesBeijing 100101China School of Chemistry and Molecular Biosciences The University of QueenslandBrisbaneQueensland 4072Australia CAS Center for Excellence in Molecular Cell Science Shanghai Institute of Biochemistry and Cell BiologyChinese Academy of SciencesShanghai 200031China University of Chinese Academy of Sciences Beijing 100101China Shanghai Clinical Research and Trial Center Shanghai 201210China

The adenosine 5'-triphosphate(ATP)-binding cassette(ABC)transporter,IrtAB,plays a vital role in the replication and viability of mycobacterium tuberculosis(Mtb),where its function is to import iron-loaded ***,it adopts the canonical type IV exporter ***,we report the structure of unliganded Mtb IrtAB and its structure in complex with ATP,ADP,or ATP analogue(AMP-PNP)at resolutions ranging from 2.8 to 3.5Å.The structure of IrtAB bound ATP-Mg2+shows a“head-to-tail”dimer of nucleotide-binding domains(NBDs),a closed amphipathic cavity within the transmembrane domains(TMDs),and a metal ion liganded to three histidine residues of IrtA in the ***-electron microscopy(Cryo-EM)structures and ATP hydrolysis assays show that the NBD of IrtA has a higher affinity for nucleotides and increased ATPase activity compared with ***,the metal ion located in the TM region of IrtA is critical for the stabilization of the conformation of IrtAB during the transport *** study provides a structural basis to explain the ATP-driven conformational changes that occur in IrtAB.

关键词： ABC exporter-like importer iron-loaded siderophore IrtAB mycobacterium tuberculosis ABC transporter

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