Objective China is among the 30 countries with a high burden of tuberculosis(TB)worldwide,and TB remains a public health concern.Kashgar Prefecture in the southern Xinjiang Autonomous Region is considered as one of th...Objective China is among the 30 countries with a high burden of tuberculosis(TB)worldwide,and TB remains a public health concern.Kashgar Prefecture in the southern Xinjiang Autonomous Region is considered as one of the highest TB burden regions in China.However,molecular epidemiological studies of Kashgar are lacking.Methods A population-based retrospective study was conducted using whole-genome sequencing(WGS)to determine the characteristics of drug resistance and the transmission patterns.Results 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 cases.Known 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%,P<0.001.The estimated proportion of recent transmissions was 25.9%(432/1,668).Multivariate logistic analyses indicated that sex,age,occupation,lineage,and drug resistance were the risk factors for recent transmission.Despite the low rate of drug resistance,drug-resistant strains had a higher risk of recent transmission than the susceptible strains(adjusted odds ratio,1.414;95%CI,1.023–1.954;P=0.036).Among all patients with drug-resistant tuberculosis(DR-TB),78.4%(171/218)were attributed to the transmission of DR-TB strains.Conclusion 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.展开更多
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 mit...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.展开更多
Objective:To analyze the mutation characteristics of inhA and katG genes in isoniazid-resistant Mycobacterium tuberculosis in Xinjiang.Methods:The katG and inhA in 148 strains of isoniazid-resistant Mycobacterium tube...Objective:To analyze the mutation characteristics of inhA and katG genes in isoniazid-resistant Mycobacterium tuberculosis in Xinjiang.Methods: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 compared.Results: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%,respectively.There 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%,respectively.The Hui and other ethnic groups were all affected by the katG gene mutation.There 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%,respectively.The mutation rates of the inhA gene in different regions were statistically different(c^(2)=6.381,P<0.05).There was no significant difference in the inhA mutation rate between patients from southern and northern Xinjiang(c^(2)=2.214,P>0.05)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,P<0.05).The mutation rates of the katG gene in southern Xinjiang,northern Xinjiang,and other provinces were 81.40%,87.63%,and 62.50%,respectively.There was no significant difference in the mutation rates of the katG gene among different regions(c^(2)=3.989,P>0.05).Conclusion:katG gene mutation was predominant in isoniazid-resistant tuberculosis patients in Xinjiang Uygur Autonomous Region,and inhA and katG gene mutation were no different among different ethnic groups.展开更多
The serine proteases of Mycobacteria tuberculosis(Mtb)are important contributors to the process of bacterial invasion and its pathogenesis.In the present study,we systematically characterized the role of the Rv1043c p...The serine proteases of Mycobacteria tuberculosis(Mtb)are important contributors to the process of bacterial invasion and its pathogenesis.In the present study,we systematically characterized the role of the Rv1043c protein in Mycobacterium infection by purifying the Rv1043c protein in Escherichia coli and constructing a Mycobacterium smegmatis(Msg)strain overexpressing Rv1043c(Msg_Rv1043c).We found that Rv1043c had serine protease activity and localized to the surface of Mtb.We determined that the optimal pH and temperature for the Rv1043c serine protease were 9.0 and 45°C,respectively.Moreover,the serine protease activity of Rv1043c was enhanced by divalent metal ions of Ca^(2+)and Mg^(2+).Site-directed mutagenesis studies demonstrated that the serine 279 residue in Rv1043c plays a catalytic role.Additionally,mouse model studies confirmed that Rv1043c significantly enhanced the survival of Msg in vivo,induced pulmonary injury and lung cell apoptosis,and promoted the release of pro-inflammatory cytokines interleukin-1βand interleukin-6 in mice.This study presents novel insights into the relationship between mycobacterial serine protease and the pathogenesis of the disease.展开更多
BACKGROUND The thoracic wall lesions,particularly chest wall tuberculosis,and chest wall tumors and other pyogenic wall and actinomycetes infections,almost always present as a diagnostic challenge.AIM To explore the v...BACKGROUND The thoracic wall lesions,particularly chest wall tuberculosis,and chest wall tumors and other pyogenic wall and actinomycetes infections,almost always present as a diagnostic challenge.AIM To explore the value of ultrasound-guided biopsy combined with the Xpert Mycobacterium tuberculosis/resistance to rifampin(MTB/RIF)assay to diagnose chest wall tuberculosis.METHODS We performed a retrospective study of patients with chest wall lesions from March 2018 to March 2021.All patients received the ultrasound-guided biopsy for pathology examination,acid-fast Bacillus staining,mycobacterial culture,and Xpert MTB/RIF analysis.The sensitivity,specificity,and area under the curve(AUC)were calculated for these diagnostic tests,either individually or combined.Rifampicin resistance results were compared between the mycobacterial culture and the Xpert MTB/RIF assay.RESULTS In 31 patients with the chest wall lesion biopsy,22 patients were diagnosed with chest wall tuberculosis.Of them,3,6,and 21 patients tested positive for mycobacterial culture,acid-fast stain,and Xpert MTB/RIF assay,respectively.The rifampicin resistance results of the 3 culture-positive patients were consistent with their Xpert MTB/RIF assay results.When considering the sensitivity,specificity,and AUC value,the Xpert MTB/RIF assay(95.5%,88.9%,and 0.92,respectively)was a better choice than the acid-fast Bacillus stain(27.3%,100.0%,and 0.64,respectively)and mycobacterial culture(13.6%,100.0%,0.57,respectively).No complications were reported during the procedure.CONCLUSION Ultrasound guided biopsy combined with Xpert MTB/RIF has high value in the diagnosis of chest wall tuberculosis,and can also detect rifampicin resistance.展开更多
Tuberculosis(TB)is a chronic infectious disease caused by Mycobacterium Tuberculosis(MTB).It is the second largest single cause of death besides novel coronavirus pneumonia.Along with the abuse of antibiotics and exte...Tuberculosis(TB)is a chronic infectious disease caused by Mycobacterium Tuberculosis(MTB).It is the second largest single cause of death besides novel coronavirus pneumonia.Along with the abuse of antibiotics and extensive use of anti-tuberculosis drugs,multidrug-resistant(MDR)TB,drug-resistant(XDR)TB and totally drug-resistant(TDR)TB became obstacles to the tuberculosis eradication worldwide.According to the World Health Organization(WHO)statistics,China is not only a high burden tuberculosis country in the world,but also a country with a serious epidemic of MDR.Traditional drugs fail to meet the needs of tuberculosis control.Therefore,it is urgent to find new targets of anti-tuberculosis drugs and develop new anti-tuberculosis drugs.Hence,this paper systematically summarizes the mechanism of traditional and newly developed anti-tuberculosis drugs,in which stressing the research progress of drug resistance mechanisms.This work provides us with new insights of new anti-tuberculosis drug developments,and may contribute to a reduction in the harm that tuberculosis brings to society.展开更多
Microscopy-positive and drug-resistant pulmonary tuberculosis (MPT+) is one of the most feared diseases due to the cost of its management and the associated mortality. The GeneXpert, a new molecular test, is in greate...Microscopy-positive and drug-resistant pulmonary tuberculosis (MPT+) is one of the most feared diseases due to the cost of its management and the associated mortality. The GeneXpert, a new molecular test, is in greater demand for the diagnosis of MPT+ resistance cases. The application of GeneXpert to new cases of MPT+ is not effective in the country’s TB screening centres. The objective of this study is to assess the contribution of GeneXpert to the determination of MPT+ resistance cases in Bangui. The study was cross-sectional and covered the period from February to July 2022. The diagnosis of tuberculosis was first performed by microscopy with Ziehl Neelsen hot stain. The GeneXpert was then used to test for resistance in the sputum of all patients with positive microscopy. The collected data was entered into Excel 2013 and analysed with Epi Info 3.3.7. We analysed data from 755 patients, 80 of whom had resistance. The 80 patients ranged in age from 6 to 68 years (mean age = 35 years). The prevalence of resistant TB was 10.60% (80/755). Primary resistance accounted for 73.75% and secondary resistance for 26.25%. The age group 20 - 39 years (57.50%), male (72.50%), 8th district (17.50%), people living in couples (53.75%), farmers (13.75%) were the socio-demographic characteristics most affected by resistance. Treatment failure (13.75%), relapses (13.75%), the notion of contagion (28.75%), a history of smoking (40%) and alcohol (61.25%) were the clinical antecedents reported by the patients. Treatment failure and relapse were the variables associated with the occurrence of resistant PMT+ (p 0.05). A considerable proportion of the overall Mycobacterium tuberculosis resistance to anti-tuberculosis drugs (10.60%) was identified by GeneXpert. Treatment failure and relapse were the factors associated with the risk of resistance.展开更多
Objective: To characterize the immunogenicity and the induction of cross-reactive responses against Mycobacterium tuberculosis(M. tuberculosis) of a proteoliposome(PL)from Mycobacterium bovis Bacillus Calmette–Guerin...Objective: To characterize the immunogenicity and the induction of cross-reactive responses against Mycobacterium tuberculosis(M. tuberculosis) of a proteoliposome(PL)from Mycobacterium bovis Bacillus Calmette–Guerin(BCG) with and without alum hydroxide(AL) as adjuvant(PLBCG-AL and PLBCG, respectively) in BALB/c mice.Methods: BALB/c mice were inoculated with phosphate buffer solution, BCG, PLBCG and PLBCG-AL. The humoral immunogenicity was determined by ELISA [immunoglobulin G(Ig G), Ig G1 and Ig G2a] and the cellular immunogenicity was evaluated in vivo by delayed type hypersensitivity. The humoral cross-reactive response against M. tuberculosis was determined by Western blot.Results: Sera from animals immunized with PLBCG-AL and PLBCG showed significant increase in specific total Ig G and Ig G1 antibodies and the presence of cross-reactive antibodies against M. tuberculosis antigens, which were more intense with the use of alum as adjuvant. Mice immunized with PLBCG and PLBCG-AL also showed a specific cellular response in vivo.Conclusions: The cellular and humoral immunogenicity of PLBCG and the capacity to induce cross-reactive responses against M. tuberculosis is in agreement with the protective capacity previously demonstrated by this vaccine candidate and supports the continuation of its evaluation in further stages.展开更多
Multiple studies elucidated the importance of cellular immune mechanisms for protection against Mycobacterium tuberculosis. However, recent studies showed that B lymphocytes play a role that is underestimated through ...Multiple studies elucidated the importance of cellular immune mechanisms for protection against Mycobacterium tuberculosis. However, recent studies showed that B lymphocytes play a role that is underestimated through various interactions with cellular immune response,forming an important aspect of host defense against M. tuberculosis bacteria. Therefore,the author hereby proposes a progressive perspective for immunology of tuberculosis,i.e., cellular immunity and humoral immunity are not necessarily mutually exclusive. The present study summarizes recent studies that support the important role of B lymphocytes in terms of M. tuberculosis infection.展开更多
MicroRNAs(miRNAs),small non-coding RNAs,play important roles in regulating host defense against pathogenic infections.This review provides information on the role of miRNAs in the antimycobacterial immune response and...MicroRNAs(miRNAs),small non-coding RNAs,play important roles in regulating host defense against pathogenic infections.This review provides information on the role of miRNAs in the antimycobacterial immune response and summarizes their possible diagnostic utility.It was compiled using scientific literature retrieved from such databases as PubMed,Scopus,ScienceDirect,Google Scholar,and PubMed Central.Relevant articles published in the English language until December 2020 were taken into consideration.It has been revealed that specific host miRNAs induced by Mycobacterium tuberculosis can target diverse factors and pathways in immune signaling to ensure longer pathogen survival inside the phagocytes.The potential use of miRNAs in tuberculosis diagnosis or therapeutic strategies has been attracting increasing attention in recent years.However,despite considerable efforts devoted to miRNA profiling,further studies are needed to elucidate the full potential of miRNAs as novel tuberculosis biomarkers or therapeutic targets.展开更多
Extracellular vesicles(EVs)are cystic vesicles naturally released by most mammalian cells and bacteria.EV contents include proteins,lipids,and nucleic acids.EVs can act as messengers to transmit a variety of molecules...Extracellular vesicles(EVs)are cystic vesicles naturally released by most mammalian cells and bacteria.EV contents include proteins,lipids,and nucleic acids.EVs can act as messengers to transmit a variety of molecules to recipient cells and thus play important regulatory roles in intercellular signal transduction.EVs,released by either a host cell or a pathogen,can carry pathogen-associated antigens and thus act as modulators of immune responses.EVs derived from Mycobacterium tuberculosis(Mtb)-infected cells can regulate the innate immune response through various pathways,such as regulating the release of inflammatory cytokines.In addition,EVs can mediate antigen presentation and regulate the adaptive immune response by transmitting immunoregulatory molecules to T helper cells.In this review,we summarize the regulatory roles of EVs in the immune response against Mtb.展开更多
BACKGROUND With the increasing prevalence of human immunodeficiency virus(HIV),the incidence of Mycobacterium tuberculosis(M.tuberculosis)bacteremia has also increased.As a common affliction of acquired immunodeficien...BACKGROUND With the increasing prevalence of human immunodeficiency virus(HIV),the incidence of Mycobacterium tuberculosis(M.tuberculosis)bacteremia has also increased.As a common affliction of acquired immunodeficiency syndrome patients,M.tuberculosis infection is associated in these patients with severe sepsis and high mortality.In contrast,M.tuberculosis bacteremia is rarely seen in HIVnegative patients,and M.tuberculosis has never been reported from the blood of patients with liver cirrhosis.CASE 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 fever.Based on these indicators of abnormal inflammation and fever,we suspected the presence of an infection.Although evidence of microbial infection was not found in routine clinical tests and the patient did not show typical clinical symptoms of infection with M.tuberculosis,next-generation sequencing of blood samples nevertheless demonstrated the presence of M.tuberculosis,which was subsequently isolated from blood samples grown in conventional Bac T/ALERT FA blood culture bottles.CONCLUSION Our findings demonstrate that HIV-negative liver cirrhosis patients can also be infected with M.tuberculosis.展开更多
Enhancement of the Human Immunodeficiency Virus (HIV) specific cytotoxic T-cells mechanisms in an HIV-1 and Mycobacterium tuberculosis (Mtb) co-infected individual seems to improve the clinical picture of an individua...Enhancement of the Human Immunodeficiency Virus (HIV) specific cytotoxic T-cells mechanisms in an HIV-1 and Mycobacterium tuberculosis (Mtb) co-infected individual seems to improve the clinical picture of an individual by reducing Acquired Immuno Deficiency Syndrome (AIDS) state progression rate. In this paper, we develop a system of deterministic differential equations representing the immune cells involved in an HIV-1 and Mtb co-infected individual. Results show that although the non-lytic arm of the HIV-1 cytotoxic T-cells affects the co-infection dynamics more than the lytic factors, a combination of both factors results in a more positive reduced progression to the AIDS state. This is due to the increased protection of the CD4<sup>+</sup> T-cells by the CTL mechanisms by further reducing infections and replications by the HIV. Thus, HIV-1 specific CTLs mechanisms’ involvement is here recommended to be part of a solution to the HIV and Mtb co-infection problems.展开更多
Mycobacterium tuberculosis(Mtb),the pathogen of tuberculosis,has latently infected about one-third of the world's population and may lead to severe clinical symptoms and death.The WhiB4 protein,a transcription fac...Mycobacterium tuberculosis(Mtb),the pathogen of tuberculosis,has latently infected about one-third of the world's population and may lead to severe clinical symptoms and death.The WhiB4 protein,a transcription factor,plays a crucial role in the survival and pathology of Mtb.WhiB4 leads to the condensation of mycobacterial nucleoids and regulates the expression of genes involved in central metabolism,respiration,and maintaining redox homeostasis.Here,we report the solution structure of reduced apo-WhiB4 monomer,which consists of an unstructured N-terminal domain with four cysteine residues and a helix-turnhelix C-terminal domain that plays a major role in DNA binding.The C-terminal domain of WhiB4 binds DNA at the minor groove,with five positively charged lysine/arginine residues contacting DNA sugar-phosphate backbones through electrostatic interactions.AT-rich DNA sequences with narrower minor grooves are more preferred by WhiB4.The binding affinity of a single C-terminal domain of WhiB4 is weak.When oxidized,WhiB4 can form dimers and oligomers in different forms through disulfide bonds,which should significantly enhance its DNA binding ability through multivalent effect and change the local structure of target genes and influence their transcription.These structural features form the basis for WhiB4 to function as a redox-sensitive transcription factor in Mtb.展开更多
This work was carried out on a series of twenty-two (22) benzimidazole derivatives with inhibitory activities against Mycobacterium tuberculosis H37Rv by applying the Quantitative Structure-Activity Relationship (QSAR...This work was carried out on a series of twenty-two (22) benzimidazole derivatives with inhibitory activities against Mycobacterium tuberculosis H37Rv by applying the Quantitative Structure-Activity Relationship (QSAR) method. The molecules were optimized at the level DFT/B3LYP/6-31 + G (d, p), to obtain the molecular descriptors. We used three statistical learning tools namely, the linear multiple regression (LMR) method, the nonlinear regression (NLMR) and the artificial neural network (ANN) method. These methods allowed us to obtain three (3) quantitative models from the quantum descriptors that are, chemical potential (μ), polarizability (α), bond length l (C = N), and lipophilicity. These models showed good statistical performance. Among these, the ANN has a significantly better predictive ability R<sup>2</sup> = 0.9995;RMSE = 0.0149;F = 31879.0548. The external validation tests verify all the criteria of Tropsha et al. and Roy et al. Also, the internal validation tests show that the model has a very satisfactory internal predictive character and can be considered as robust. Moreover, the applicability range of this model determined from the levers shows that a prediction of the pMIC of the new benzimidazole derivatives is acceptable when its lever value is lower than 1.展开更多
The aim of this study was to investigate the usefulness of combining profiles obtained by using a line probe assay (LPA) originally intended to characterize the resistance of two major anti-tuberculosis drugs to the a...The aim of this study was to investigate the usefulness of combining profiles obtained by using a line probe assay (LPA) originally intended to characterize the resistance of two major anti-tuberculosis drugs to the association of spoligotyping and MIRU-VNTR, in order to improve its discriminatory power. For this purpose, 74 strains of Mycobacterium tuberculosis belonging to the same cluster after spoligotyping were further typed by using the 24 loci MIRU/VNTR. These strains were then tested by the GenoType MTBDRplus, and profiles obtained were analyzed within previously obtained clusters. The combination of spoligotying and MIRU-VNTR led to the consolidation of 56 of them (75.7%) in 9 clusters. Most of the strains (54, 96.4%) were multidrug resistant (MDR). From the 9 initial clusters, the addition of GenoType MTBDRplus helped to define 26 profiles including 11 unique profiles, and 3 original clusters remained undifferentiated. Results obtained express the relevance of combining this method which improved quite significantly the discriminatory power in typing Mycobacterium tuberculosis.展开更多
Granulocytic or myeloid sarcoma (MS) is a rare neoplastic condition consisting of a tumor mass of myeloid blasts with or without maturation occurring at an anatomical site other than the bone marrow the association be...Granulocytic or myeloid sarcoma (MS) is a rare neoplastic condition consisting of a tumor mass of myeloid blasts with or without maturation occurring at an anatomical site other than the bone marrow the association between tuberculosis and MS is extremely rare. A 21-year-old female patient presented cough, sore throat and a suppurative swollen gum for 10 days prior to hospital admission. Physical examination revealed moderate pallor and swollen inferior gum. CBC revealed Hb6.5 g/dL, hematocrit 18.4% MCV 97 fL MCH 34 pg, WBC 18.5 ′ 109/μL (1 My/3 Bt/69 Sg/1 Eo/0 Ba/20 Ly/6 Mo), Platelets 43 ′ 109/μL. The peripheral blood smear presented with 3% blast cells (type 1) and granulocytic dysplasia. Bone marrow biopsy showed 100% cellularity. 50% of cells were from granulocytic precursors, diagnosis of granulocytic sarcoma. The diagnosis of AML was established: granulocytic sarcoma with massive gum infiltration (immature granulocytic cells) and 10% of blasts in bone marrow. The patient received induction chemotherapy (3 + 7 daunorubicin 90 mg/m2), and gum tissue culture was positive for Mycobacterium tuberculosis. Simultaneously, a qRT- PCR test confirmed the same bacteria in the gum tissue. Patient treated with isoniazid, rifampicin, pyrazinamide and ethambutol ciprofloxacin and amikacin). Remission was achieved and the patient was submitted for consolidation/ intensification (HiDAC x3) schema and referred to allogeneic HSCT. After induction and full hematological recovery there was no further evidence or recurrence of fever and lytic lesions. Currently patient is under CR and ling follow up (48 months) did not show recurrence of either AML or tuberculosis.展开更多
Tuberculosis(TB)is a chronic infectious disease,which is caused by the pathogen Mycobacterium tuberculosis(Mtb)and reemerged as a global health risk with a significant proportion of multi-drug resistant and extensivel...Tuberculosis(TB)is a chronic infectious disease,which is caused by the pathogen Mycobacterium tuberculosis(Mtb)and reemerged as a global health risk with a significant proportion of multi-drug resistant and extensively drug resistant TB cases.It is very urgent to find some novel high-confidence drug targets in Mtb for discovering the effective anti-TB agents.Thioredoxin reductase(TrxR)has been identified to be a highly viable target for anti-TB drugs for its important role in protecting the pathogen from thiol-specific oxidizing stress,regulating intracellular dithiol/disulfide homeostasis and DNA replication and repair.In the present work,a near-infrared(NIR)fluorescent probe DDAT was developed for the detection of TrxR activity and used to high-throughput screen the TrxR inhibitors from natural products.Two screened TrxR inhibitors from Sappan Lignum and microbial metabolites that were further used to inhibit Mycobacterium tuberculosis.All the results indicate that DDAT is a practical fluorescent molecular tool for the discovery of potential anti-TB drugs.展开更多
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 sideroph...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 siderophores.Unusually,it adopts the canonical type IV exporter fold.Herein,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 cavity.Cryo-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 IrtB.Moreover,the metal ion located in the TM region of IrtA is critical for the stabilization of the conformation of IrtAB during the transport cycle.This study provides a structural basis to explain the ATP-driven conformational changes that occur in IrtAB.展开更多
Objective: The increase in the development of resistance to multiple drugs in mycobacterium tuberculosis(MTB) poses a substantial obstacle to the prevention and management of tuberculosis(TB). A thorough investigation...Objective: The increase in the development of resistance to multiple drugs in mycobacterium tuberculosis(MTB) poses a substantial obstacle to the prevention and management of tuberculosis(TB). A thorough investigation of the genotypes linked to multidrug resistance is crucial for comprehending the mechanisms underlying drug resistance. The objective of this research was to assess the attributes of gene mutations associated with multidrug resistance in clinical isolates of mycobacterium tuberculosis through the utilization of whole-genome sequencing. Methods: A total of 124 strains of drug-resistant mycobacterium tuberculosis were collected, and the genomic DNA of both multidrug-resistant and rifampin-resistant strains were extracted and sequenced. Bioinformatics was used to analyze and compare multidrug resistance-related gene sequences in order to detect the variation of multidrug resistance genes. Results: The results revealed that the resistance spectrum of XDR-TB group was much wider than that of the other three groups, with the RR-TB group having the most limited resistance spectrum.Within the MDR-TB strains, fabG1 exhibited the highest frequency of mutations, while RRS, gyrA, and rpoB were identified as the predominant mutation bases in XDR-TB strains. Additionally, rpoB emerged as the primary mutation base in MDR-TB and RR-TB strains. Notably, the fabG1 mutation was found to be closely associated with PDR-TB. Furthermore, the correlation between the mutation rate of rpoB and multidrug resistance was deemed to be of secondary importance. Conclusion: Various strains of MTB exhibited distinct mechanisms of drug resistance, with the gene mutations of fabG1,RRS, gyrA, and rpoB potentially playing a pivotal role in the development of drug resistance. However, the primary genes responsible for drug resistance mutations varied among different strains of TB.展开更多
基金funded by the National Key R&D Program of China [2022YFC2305200]Natural Science Foundation of Xinjiang Uygur Autonomous Region [2021A01D145 and 2022D01A115]Applied Technology Research and Development Programing Project of Kashgar Prefecture [KS2021031 and KS2021034]。
文摘Objective China is among the 30 countries with a high burden of tuberculosis(TB)worldwide,and TB remains a public health concern.Kashgar Prefecture in the southern Xinjiang Autonomous Region is considered as one of the highest TB burden regions in China.However,molecular epidemiological studies of Kashgar are lacking.Methods A population-based retrospective study was conducted using whole-genome sequencing(WGS)to determine the characteristics of drug resistance and the transmission patterns.Results 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 cases.Known 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%,P<0.001.The estimated proportion of recent transmissions was 25.9%(432/1,668).Multivariate logistic analyses indicated that sex,age,occupation,lineage,and drug resistance were the risk factors for recent transmission.Despite the low rate of drug resistance,drug-resistant strains had a higher risk of recent transmission than the susceptible strains(adjusted odds ratio,1.414;95%CI,1.023–1.954;P=0.036).Among all patients with drug-resistant tuberculosis(DR-TB),78.4%(171/218)were attributed to the transmission of DR-TB strains.Conclusion 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.
文摘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.
基金Xinjiang Uygur Autonomous Region Health Youth Medical Science and Technology Talents Special Project(Project number:WJW-202116)。
文摘Objective:To analyze the mutation characteristics of inhA and katG genes in isoniazid-resistant Mycobacterium tuberculosis in Xinjiang.Methods: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 compared.Results: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%,respectively.There 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%,respectively.The Hui and other ethnic groups were all affected by the katG gene mutation.There 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%,respectively.The mutation rates of the inhA gene in different regions were statistically different(c^(2)=6.381,P<0.05).There was no significant difference in the inhA mutation rate between patients from southern and northern Xinjiang(c^(2)=2.214,P>0.05)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,P<0.05).The mutation rates of the katG gene in southern Xinjiang,northern Xinjiang,and other provinces were 81.40%,87.63%,and 62.50%,respectively.There was no significant difference in the mutation rates of the katG gene among different regions(c^(2)=3.989,P>0.05).Conclusion:katG gene mutation was predominant in isoniazid-resistant tuberculosis patients in Xinjiang Uygur Autonomous Region,and inhA and katG gene mutation were no different among different ethnic groups.
基金This research was supported by the National Key Research and Development Program of China(2021YFD1800403)the National Natural Science Foundation of China(32273005 and 32002256).
文摘The serine proteases of Mycobacteria tuberculosis(Mtb)are important contributors to the process of bacterial invasion and its pathogenesis.In the present study,we systematically characterized the role of the Rv1043c protein in Mycobacterium infection by purifying the Rv1043c protein in Escherichia coli and constructing a Mycobacterium smegmatis(Msg)strain overexpressing Rv1043c(Msg_Rv1043c).We found that Rv1043c had serine protease activity and localized to the surface of Mtb.We determined that the optimal pH and temperature for the Rv1043c serine protease were 9.0 and 45°C,respectively.Moreover,the serine protease activity of Rv1043c was enhanced by divalent metal ions of Ca^(2+)and Mg^(2+).Site-directed mutagenesis studies demonstrated that the serine 279 residue in Rv1043c plays a catalytic role.Additionally,mouse model studies confirmed that Rv1043c significantly enhanced the survival of Msg in vivo,induced pulmonary injury and lung cell apoptosis,and promoted the release of pro-inflammatory cytokines interleukin-1βand interleukin-6 in mice.This study presents novel insights into the relationship between mycobacterial serine protease and the pathogenesis of the disease.
文摘BACKGROUND The thoracic wall lesions,particularly chest wall tuberculosis,and chest wall tumors and other pyogenic wall and actinomycetes infections,almost always present as a diagnostic challenge.AIM To explore the value of ultrasound-guided biopsy combined with the Xpert Mycobacterium tuberculosis/resistance to rifampin(MTB/RIF)assay to diagnose chest wall tuberculosis.METHODS We performed a retrospective study of patients with chest wall lesions from March 2018 to March 2021.All patients received the ultrasound-guided biopsy for pathology examination,acid-fast Bacillus staining,mycobacterial culture,and Xpert MTB/RIF analysis.The sensitivity,specificity,and area under the curve(AUC)were calculated for these diagnostic tests,either individually or combined.Rifampicin resistance results were compared between the mycobacterial culture and the Xpert MTB/RIF assay.RESULTS In 31 patients with the chest wall lesion biopsy,22 patients were diagnosed with chest wall tuberculosis.Of them,3,6,and 21 patients tested positive for mycobacterial culture,acid-fast stain,and Xpert MTB/RIF assay,respectively.The rifampicin resistance results of the 3 culture-positive patients were consistent with their Xpert MTB/RIF assay results.When considering the sensitivity,specificity,and AUC value,the Xpert MTB/RIF assay(95.5%,88.9%,and 0.92,respectively)was a better choice than the acid-fast Bacillus stain(27.3%,100.0%,and 0.64,respectively)and mycobacterial culture(13.6%,100.0%,0.57,respectively).No complications were reported during the procedure.CONCLUSION Ultrasound guided biopsy combined with Xpert MTB/RIF has high value in the diagnosis of chest wall tuberculosis,and can also detect rifampicin resistance.
基金Fundamental Research Program of Shanxi province(No.202103021223339,20210302124435)Shanxi Scholarship Council of China(No.2022-175)+1 种基金Fundamental Research Program of Shanxi Datong University(No.2019Q2,2019Q4)Doctoral Scientific Research Foundation of Shanxi Datong University(No.2018-B-13,2018-B-28)。
文摘Tuberculosis(TB)is a chronic infectious disease caused by Mycobacterium Tuberculosis(MTB).It is the second largest single cause of death besides novel coronavirus pneumonia.Along with the abuse of antibiotics and extensive use of anti-tuberculosis drugs,multidrug-resistant(MDR)TB,drug-resistant(XDR)TB and totally drug-resistant(TDR)TB became obstacles to the tuberculosis eradication worldwide.According to the World Health Organization(WHO)statistics,China is not only a high burden tuberculosis country in the world,but also a country with a serious epidemic of MDR.Traditional drugs fail to meet the needs of tuberculosis control.Therefore,it is urgent to find new targets of anti-tuberculosis drugs and develop new anti-tuberculosis drugs.Hence,this paper systematically summarizes the mechanism of traditional and newly developed anti-tuberculosis drugs,in which stressing the research progress of drug resistance mechanisms.This work provides us with new insights of new anti-tuberculosis drug developments,and may contribute to a reduction in the harm that tuberculosis brings to society.
文摘Microscopy-positive and drug-resistant pulmonary tuberculosis (MPT+) is one of the most feared diseases due to the cost of its management and the associated mortality. The GeneXpert, a new molecular test, is in greater demand for the diagnosis of MPT+ resistance cases. The application of GeneXpert to new cases of MPT+ is not effective in the country’s TB screening centres. The objective of this study is to assess the contribution of GeneXpert to the determination of MPT+ resistance cases in Bangui. The study was cross-sectional and covered the period from February to July 2022. The diagnosis of tuberculosis was first performed by microscopy with Ziehl Neelsen hot stain. The GeneXpert was then used to test for resistance in the sputum of all patients with positive microscopy. The collected data was entered into Excel 2013 and analysed with Epi Info 3.3.7. We analysed data from 755 patients, 80 of whom had resistance. The 80 patients ranged in age from 6 to 68 years (mean age = 35 years). The prevalence of resistant TB was 10.60% (80/755). Primary resistance accounted for 73.75% and secondary resistance for 26.25%. The age group 20 - 39 years (57.50%), male (72.50%), 8th district (17.50%), people living in couples (53.75%), farmers (13.75%) were the socio-demographic characteristics most affected by resistance. Treatment failure (13.75%), relapses (13.75%), the notion of contagion (28.75%), a history of smoking (40%) and alcohol (61.25%) were the clinical antecedents reported by the patients. Treatment failure and relapse were the variables associated with the occurrence of resistant PMT+ (p 0.05). A considerable proportion of the overall Mycobacterium tuberculosis resistance to anti-tuberculosis drugs (10.60%) was identified by GeneXpert. Treatment failure and relapse were the factors associated with the risk of resistance.
基金Supported by the Long-Term Research Grant Scheme Grant,Department of Higher Education,Ministry of Education,Malaysia(Grant No.203.PPSK.67212002)as well as the Ministry of Science and Technology,Cuba
文摘Objective: To characterize the immunogenicity and the induction of cross-reactive responses against Mycobacterium tuberculosis(M. tuberculosis) of a proteoliposome(PL)from Mycobacterium bovis Bacillus Calmette–Guerin(BCG) with and without alum hydroxide(AL) as adjuvant(PLBCG-AL and PLBCG, respectively) in BALB/c mice.Methods: BALB/c mice were inoculated with phosphate buffer solution, BCG, PLBCG and PLBCG-AL. The humoral immunogenicity was determined by ELISA [immunoglobulin G(Ig G), Ig G1 and Ig G2a] and the cellular immunogenicity was evaluated in vivo by delayed type hypersensitivity. The humoral cross-reactive response against M. tuberculosis was determined by Western blot.Results: Sera from animals immunized with PLBCG-AL and PLBCG showed significant increase in specific total Ig G and Ig G1 antibodies and the presence of cross-reactive antibodies against M. tuberculosis antigens, which were more intense with the use of alum as adjuvant. Mice immunized with PLBCG and PLBCG-AL also showed a specific cellular response in vivo.Conclusions: The cellular and humoral immunogenicity of PLBCG and the capacity to induce cross-reactive responses against M. tuberculosis is in agreement with the protective capacity previously demonstrated by this vaccine candidate and supports the continuation of its evaluation in further stages.
文摘Multiple studies elucidated the importance of cellular immune mechanisms for protection against Mycobacterium tuberculosis. However, recent studies showed that B lymphocytes play a role that is underestimated through various interactions with cellular immune response,forming an important aspect of host defense against M. tuberculosis bacteria. Therefore,the author hereby proposes a progressive perspective for immunology of tuberculosis,i.e., cellular immunity and humoral immunity are not necessarily mutually exclusive. The present study summarizes recent studies that support the important role of B lymphocytes in terms of M. tuberculosis infection.
文摘MicroRNAs(miRNAs),small non-coding RNAs,play important roles in regulating host defense against pathogenic infections.This review provides information on the role of miRNAs in the antimycobacterial immune response and summarizes their possible diagnostic utility.It was compiled using scientific literature retrieved from such databases as PubMed,Scopus,ScienceDirect,Google Scholar,and PubMed Central.Relevant articles published in the English language until December 2020 were taken into consideration.It has been revealed that specific host miRNAs induced by Mycobacterium tuberculosis can target diverse factors and pathways in immune signaling to ensure longer pathogen survival inside the phagocytes.The potential use of miRNAs in tuberculosis diagnosis or therapeutic strategies has been attracting increasing attention in recent years.However,despite considerable efforts devoted to miRNA profiling,further studies are needed to elucidate the full potential of miRNAs as novel tuberculosis biomarkers or therapeutic targets.
基金Natural Science Foundation of the Inner Mongolia Autonomous Region for Distinguished Young Scholars,No.2020JQ07General Programs of Natural Science Foundation of the Inner Mongolia Autonomous Region,No.2020MS08126and"Zhiyuan"Talent Project of the Inner Mongolia Medical University,No.ZY0130013.
文摘Extracellular vesicles(EVs)are cystic vesicles naturally released by most mammalian cells and bacteria.EV contents include proteins,lipids,and nucleic acids.EVs can act as messengers to transmit a variety of molecules to recipient cells and thus play important regulatory roles in intercellular signal transduction.EVs,released by either a host cell or a pathogen,can carry pathogen-associated antigens and thus act as modulators of immune responses.EVs derived from Mycobacterium tuberculosis(Mtb)-infected cells can regulate the innate immune response through various pathways,such as regulating the release of inflammatory cytokines.In addition,EVs can mediate antigen presentation and regulate the adaptive immune response by transmitting immunoregulatory molecules to T helper cells.In this review,we summarize the regulatory roles of EVs in the immune response against Mtb.
文摘BACKGROUND With the increasing prevalence of human immunodeficiency virus(HIV),the incidence of Mycobacterium tuberculosis(M.tuberculosis)bacteremia has also increased.As a common affliction of acquired immunodeficiency syndrome patients,M.tuberculosis infection is associated in these patients with severe sepsis and high mortality.In contrast,M.tuberculosis bacteremia is rarely seen in HIVnegative patients,and M.tuberculosis has never been reported from the blood of patients with liver cirrhosis.CASE 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 fever.Based on these indicators of abnormal inflammation and fever,we suspected the presence of an infection.Although evidence of microbial infection was not found in routine clinical tests and the patient did not show typical clinical symptoms of infection with M.tuberculosis,next-generation sequencing of blood samples nevertheless demonstrated the presence of M.tuberculosis,which was subsequently isolated from blood samples grown in conventional Bac T/ALERT FA blood culture bottles.CONCLUSION Our findings demonstrate that HIV-negative liver cirrhosis patients can also be infected with M.tuberculosis.
文摘Enhancement of the Human Immunodeficiency Virus (HIV) specific cytotoxic T-cells mechanisms in an HIV-1 and Mycobacterium tuberculosis (Mtb) co-infected individual seems to improve the clinical picture of an individual by reducing Acquired Immuno Deficiency Syndrome (AIDS) state progression rate. In this paper, we develop a system of deterministic differential equations representing the immune cells involved in an HIV-1 and Mtb co-infected individual. Results show that although the non-lytic arm of the HIV-1 cytotoxic T-cells affects the co-infection dynamics more than the lytic factors, a combination of both factors results in a more positive reduced progression to the AIDS state. This is due to the increased protection of the CD4<sup>+</sup> T-cells by the CTL mechanisms by further reducing infections and replications by the HIV. Thus, HIV-1 specific CTLs mechanisms’ involvement is here recommended to be part of a solution to the HIV and Mtb co-infection problems.
基金grant 2016YFA0501202 from the Ministry of Science and Technologygrant 31570734 from the National Natural Science Foundation of China,and grant 2018YFD0500900 from National Key R&D Program of China.
文摘Mycobacterium tuberculosis(Mtb),the pathogen of tuberculosis,has latently infected about one-third of the world's population and may lead to severe clinical symptoms and death.The WhiB4 protein,a transcription factor,plays a crucial role in the survival and pathology of Mtb.WhiB4 leads to the condensation of mycobacterial nucleoids and regulates the expression of genes involved in central metabolism,respiration,and maintaining redox homeostasis.Here,we report the solution structure of reduced apo-WhiB4 monomer,which consists of an unstructured N-terminal domain with four cysteine residues and a helix-turnhelix C-terminal domain that plays a major role in DNA binding.The C-terminal domain of WhiB4 binds DNA at the minor groove,with five positively charged lysine/arginine residues contacting DNA sugar-phosphate backbones through electrostatic interactions.AT-rich DNA sequences with narrower minor grooves are more preferred by WhiB4.The binding affinity of a single C-terminal domain of WhiB4 is weak.When oxidized,WhiB4 can form dimers and oligomers in different forms through disulfide bonds,which should significantly enhance its DNA binding ability through multivalent effect and change the local structure of target genes and influence their transcription.These structural features form the basis for WhiB4 to function as a redox-sensitive transcription factor in Mtb.
文摘This work was carried out on a series of twenty-two (22) benzimidazole derivatives with inhibitory activities against Mycobacterium tuberculosis H37Rv by applying the Quantitative Structure-Activity Relationship (QSAR) method. The molecules were optimized at the level DFT/B3LYP/6-31 + G (d, p), to obtain the molecular descriptors. We used three statistical learning tools namely, the linear multiple regression (LMR) method, the nonlinear regression (NLMR) and the artificial neural network (ANN) method. These methods allowed us to obtain three (3) quantitative models from the quantum descriptors that are, chemical potential (μ), polarizability (α), bond length l (C = N), and lipophilicity. These models showed good statistical performance. Among these, the ANN has a significantly better predictive ability R<sup>2</sup> = 0.9995;RMSE = 0.0149;F = 31879.0548. The external validation tests verify all the criteria of Tropsha et al. and Roy et al. Also, the internal validation tests show that the model has a very satisfactory internal predictive character and can be considered as robust. Moreover, the applicability range of this model determined from the levers shows that a prediction of the pMIC of the new benzimidazole derivatives is acceptable when its lever value is lower than 1.
基金the support of the European Respiratory Society,Fellowship STRTF 413-2011.
文摘The aim of this study was to investigate the usefulness of combining profiles obtained by using a line probe assay (LPA) originally intended to characterize the resistance of two major anti-tuberculosis drugs to the association of spoligotyping and MIRU-VNTR, in order to improve its discriminatory power. For this purpose, 74 strains of Mycobacterium tuberculosis belonging to the same cluster after spoligotyping were further typed by using the 24 loci MIRU/VNTR. These strains were then tested by the GenoType MTBDRplus, and profiles obtained were analyzed within previously obtained clusters. The combination of spoligotying and MIRU-VNTR led to the consolidation of 56 of them (75.7%) in 9 clusters. Most of the strains (54, 96.4%) were multidrug resistant (MDR). From the 9 initial clusters, the addition of GenoType MTBDRplus helped to define 26 profiles including 11 unique profiles, and 3 original clusters remained undifferentiated. Results obtained express the relevance of combining this method which improved quite significantly the discriminatory power in typing Mycobacterium tuberculosis.
文摘Granulocytic or myeloid sarcoma (MS) is a rare neoplastic condition consisting of a tumor mass of myeloid blasts with or without maturation occurring at an anatomical site other than the bone marrow the association between tuberculosis and MS is extremely rare. A 21-year-old female patient presented cough, sore throat and a suppurative swollen gum for 10 days prior to hospital admission. Physical examination revealed moderate pallor and swollen inferior gum. CBC revealed Hb6.5 g/dL, hematocrit 18.4% MCV 97 fL MCH 34 pg, WBC 18.5 ′ 109/μL (1 My/3 Bt/69 Sg/1 Eo/0 Ba/20 Ly/6 Mo), Platelets 43 ′ 109/μL. The peripheral blood smear presented with 3% blast cells (type 1) and granulocytic dysplasia. Bone marrow biopsy showed 100% cellularity. 50% of cells were from granulocytic precursors, diagnosis of granulocytic sarcoma. The diagnosis of AML was established: granulocytic sarcoma with massive gum infiltration (immature granulocytic cells) and 10% of blasts in bone marrow. The patient received induction chemotherapy (3 + 7 daunorubicin 90 mg/m2), and gum tissue culture was positive for Mycobacterium tuberculosis. Simultaneously, a qRT- PCR test confirmed the same bacteria in the gum tissue. Patient treated with isoniazid, rifampicin, pyrazinamide and ethambutol ciprofloxacin and amikacin). Remission was achieved and the patient was submitted for consolidation/ intensification (HiDAC x3) schema and referred to allogeneic HSCT. After induction and full hematological recovery there was no further evidence or recurrence of fever and lytic lesions. Currently patient is under CR and ling follow up (48 months) did not show recurrence of either AML or tuberculosis.
基金the National Natural Science Foundation of China(Nos.81930112 and 82225048)Open Research Fund of the School of Chemistry and Chemical Engineering,Henan Normal University for support(No.2021YB07)Research on National Reference Material and Product Development of Natural Products(No.SG030801,Beijing Polytechnic)。
文摘Tuberculosis(TB)is a chronic infectious disease,which is caused by the pathogen Mycobacterium tuberculosis(Mtb)and reemerged as a global health risk with a significant proportion of multi-drug resistant and extensively drug resistant TB cases.It is very urgent to find some novel high-confidence drug targets in Mtb for discovering the effective anti-TB agents.Thioredoxin reductase(TrxR)has been identified to be a highly viable target for anti-TB drugs for its important role in protecting the pathogen from thiol-specific oxidizing stress,regulating intracellular dithiol/disulfide homeostasis and DNA replication and repair.In the present work,a near-infrared(NIR)fluorescent probe DDAT was developed for the detection of TrxR activity and used to high-throughput screen the TrxR inhibitors from natural products.Two screened TrxR inhibitors from Sappan Lignum and microbial metabolites that were further used to inhibit Mycobacterium tuberculosis.All the results indicate that DDAT is a practical fluorescent molecular tool for the discovery of potential anti-TB drugs.
基金supported by grants from the National Key Research and Development Program of China(Grant No.2022YFC2302900)the National Natural Science Foundation of China(Grant No.32171217 to B.Z.)+5 种基金Shanghai Sailing Program(Grant No.21YF1429700 to B.Z.)Young Elite Scientists Sponsorship Program by CAST(Grant No.2021QNRC001)the Lingang Laboratory(Grant No.LG202101-01-08)Shanghai Municipal Science and Technology Major Project(Grant No.ZD2021CY001)Science and Technology Commission of Shanghai Municipality(Grant No.20XD1422900 to H.Y.)the Shanghai Frontiers Science Center for Biomacromolecules and Precision Medicine,Shanghaitech University.
文摘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 siderophores.Unusually,it adopts the canonical type IV exporter fold.Herein,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 cavity.Cryo-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 IrtB.Moreover,the metal ion located in the TM region of IrtA is critical for the stabilization of the conformation of IrtAB during the transport cycle.This study provides a structural basis to explain the ATP-driven conformational changes that occur in IrtAB.
文摘Objective: The increase in the development of resistance to multiple drugs in mycobacterium tuberculosis(MTB) poses a substantial obstacle to the prevention and management of tuberculosis(TB). A thorough investigation of the genotypes linked to multidrug resistance is crucial for comprehending the mechanisms underlying drug resistance. The objective of this research was to assess the attributes of gene mutations associated with multidrug resistance in clinical isolates of mycobacterium tuberculosis through the utilization of whole-genome sequencing. Methods: A total of 124 strains of drug-resistant mycobacterium tuberculosis were collected, and the genomic DNA of both multidrug-resistant and rifampin-resistant strains were extracted and sequenced. Bioinformatics was used to analyze and compare multidrug resistance-related gene sequences in order to detect the variation of multidrug resistance genes. Results: The results revealed that the resistance spectrum of XDR-TB group was much wider than that of the other three groups, with the RR-TB group having the most limited resistance spectrum.Within the MDR-TB strains, fabG1 exhibited the highest frequency of mutations, while RRS, gyrA, and rpoB were identified as the predominant mutation bases in XDR-TB strains. Additionally, rpoB emerged as the primary mutation base in MDR-TB and RR-TB strains. Notably, the fabG1 mutation was found to be closely associated with PDR-TB. Furthermore, the correlation between the mutation rate of rpoB and multidrug resistance was deemed to be of secondary importance. Conclusion: Various strains of MTB exhibited distinct mechanisms of drug resistance, with the gene mutations of fabG1,RRS, gyrA, and rpoB potentially playing a pivotal role in the development of drug resistance. However, the primary genes responsible for drug resistance mutations varied among different strains of TB.
