Pub Date : 2024-12-24DOI: 10.1016/j.tube.2024.102594
Maxwell T Stevens, Paige M E Hawkins, Trixie Wang, Richard J Payne, Warwick J Britton
Multi-drug-resistant Mycobacterium tuberculosis is an escalating global health problem, and a strong pipeline of novel compounds is needed to combat rising antimicrobial resistance. Ecumicin is a novel analogue of the natural antimycobacterial cyclic peptide ecumicin, with selective activity against Mycobacterium species. The activity of ecumicin∗ was compared to that of frontline tuberculosis therapies under in vitro conditions representative of niches where M. tuberculosis resides in the human lung. M. tuberculosis expressing luciferase was cultured in defined 7H9-based media containing glucose, butyrate, valerate, acidified glucose, low or high cholesterol concentrations, or intracellularly in human THP-1 and mouse RAW264.7 macrophages. Ecumicin∗ effectively killed M. tuberculosis under all assay conditions. The IC90 of ecumicin∗ was increased in acidified 7H9 media, and both IC90 and AUC90 values were increased in valerate, cholesterol, high cholesterol culture media. In time-kill assays, anti-M. tuberculosis activity of ecumicin∗ was sustained for 28 days. By comparison, IC50 and IC90 of isoniazid were decreased in butyrate and cholesterols medias, and mycobacterial regrowth occurred in glucose and cholesterol culture medias within 14 days at high isoniazid concentrations. Ecumicin∗ inhibited M. tuberculosis growth in THP-1 macrophages, and at higher IC90 in mouse RAW264.7 macrophages. Drug testing under disease-relevant conditions is important prior to in vivo examination, and ecumicin∗ has proven effective in multiple in vitro conditions typical of the lung environment of tuberculosis patients.
{"title":"Analogue of the natural product ecumicin causes sustained growth inhibition of Mycobacterium tuberculosis under multiple growth conditions.","authors":"Maxwell T Stevens, Paige M E Hawkins, Trixie Wang, Richard J Payne, Warwick J Britton","doi":"10.1016/j.tube.2024.102594","DOIUrl":"https://doi.org/10.1016/j.tube.2024.102594","url":null,"abstract":"<p><p>Multi-drug-resistant Mycobacterium tuberculosis is an escalating global health problem, and a strong pipeline of novel compounds is needed to combat rising antimicrobial resistance. Ecumicin is a novel analogue of the natural antimycobacterial cyclic peptide ecumicin, with selective activity against Mycobacterium species. The activity of ecumicin∗ was compared to that of frontline tuberculosis therapies under in vitro conditions representative of niches where M. tuberculosis resides in the human lung. M. tuberculosis expressing luciferase was cultured in defined 7H9-based media containing glucose, butyrate, valerate, acidified glucose, low or high cholesterol concentrations, or intracellularly in human THP-1 and mouse RAW264.7 macrophages. Ecumicin∗ effectively killed M. tuberculosis under all assay conditions. The IC<sub>90</sub> of ecumicin∗ was increased in acidified 7H9 media, and both IC<sub>90</sub> and AUC<sub>90</sub> values were increased in valerate, cholesterol, high cholesterol culture media. In time-kill assays, anti-M. tuberculosis activity of ecumicin∗ was sustained for 28 days. By comparison, IC<sub>50</sub> and IC<sub>90</sub> of isoniazid were decreased in butyrate and cholesterols medias, and mycobacterial regrowth occurred in glucose and cholesterol culture medias within 14 days at high isoniazid concentrations. Ecumicin∗ inhibited M. tuberculosis growth in THP-1 macrophages, and at higher IC<sub>90</sub> in mouse RAW264.7 macrophages. Drug testing under disease-relevant conditions is important prior to in vivo examination, and ecumicin∗ has proven effective in multiple in vitro conditions typical of the lung environment of tuberculosis patients.</p>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"151 ","pages":"102594"},"PeriodicalIF":2.8,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142932802","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-20DOI: 10.1016/j.tube.2024.102595
Petter Holmberg, Martina Janoušková, Tobias Schmidt, Ariane Neumann, Oskar Olsson, Per-Erik Isberg, Maja Reimann, Kristian Riesbeck, Sten Skogmar, Per Björkman
Background: Interferon-γ release assays (IGRAs) for tuberculosis infection (TBI) cannot distinguish different stages of the TBI spectrum (including spontaneously cleared infection). We investigated patterns of Mtb-specific blood mediators in people with and without TBI during tuberculosis preventive therapy (TPT).
Methods: Individuals with likelihood of recent Mtb exposure, aged 15-25 years, with valid IGRA results, in whom tuberculosis (TB) had been excluded, were included. Persons with TBI were sampled prior to TPT (IGRA + pre-treatment, n = 15) or after completion of TPT (IGRA + post-treatment, n = 15). Five persons without TBI were included as controls (IGRA-). Levels of 40 mediators related to TB immune control in blood incubated with Mtb antigens in the QuantiFERON-TB Plus® kit were assessed with electrochemiluminescence assay and compared between participant categories.
Results: The concentration of 10 mediators (GM-CSF, interferon-γ, IL-2, I-TAC, IL-12, IP-10, I-309, MCP-2, MIG, and VEGF) significantly differed between IGRA + pre-treatment and IGRA-. A non-significant trend in levels of these markers was observed between IGRA + pre-treatment, IGRA + post-treatment and IGRA-. Based on these mediators two clusters were identified: A (n = 16), including 5 IGRA-, 4 IGRA + pre-treatment, 7 IGRA + post-treatment and B (n = 19), including 11 IGRA + pre-treatment and 8 IGRA + post-treatment.
Conclusion: Plasma levels of several Mtb-triggered mediators differed with regard to TBI status among persons recently exposed to TB, suggesting the potential for alternative markers to assess TBI status. Longitudinal analysis of these mediators during TPT is warranted to explore whether these markers can be used to assess likelihood of persistence of viable bacilli in Mtb-exposed individuals.
{"title":"Blood levels of Mycobacterium tuberculosis (Mtb)antigen-triggered immune markers in people exposed to tuberculosis with regard to Mtb infection status and receipt of tuberculosis preventive therapy.","authors":"Petter Holmberg, Martina Janoušková, Tobias Schmidt, Ariane Neumann, Oskar Olsson, Per-Erik Isberg, Maja Reimann, Kristian Riesbeck, Sten Skogmar, Per Björkman","doi":"10.1016/j.tube.2024.102595","DOIUrl":"https://doi.org/10.1016/j.tube.2024.102595","url":null,"abstract":"<p><strong>Background: </strong>Interferon-γ release assays (IGRAs) for tuberculosis infection (TBI) cannot distinguish different stages of the TBI spectrum (including spontaneously cleared infection). We investigated patterns of Mtb-specific blood mediators in people with and without TBI during tuberculosis preventive therapy (TPT).</p><p><strong>Methods: </strong>Individuals with likelihood of recent Mtb exposure, aged 15-25 years, with valid IGRA results, in whom tuberculosis (TB) had been excluded, were included. Persons with TBI were sampled prior to TPT (IGRA + pre-treatment, n = 15) or after completion of TPT (IGRA + post-treatment, n = 15). Five persons without TBI were included as controls (IGRA-). Levels of 40 mediators related to TB immune control in blood incubated with Mtb antigens in the QuantiFERON-TB Plus® kit were assessed with electrochemiluminescence assay and compared between participant categories.</p><p><strong>Results: </strong>The concentration of 10 mediators (GM-CSF, interferon-γ, IL-2, I-TAC, IL-12, IP-10, I-309, MCP-2, MIG, and VEGF) significantly differed between IGRA + pre-treatment and IGRA-. A non-significant trend in levels of these markers was observed between IGRA + pre-treatment, IGRA + post-treatment and IGRA-. Based on these mediators two clusters were identified: A (n = 16), including 5 IGRA-, 4 IGRA + pre-treatment, 7 IGRA + post-treatment and B (n = 19), including 11 IGRA + pre-treatment and 8 IGRA + post-treatment.</p><p><strong>Conclusion: </strong>Plasma levels of several Mtb-triggered mediators differed with regard to TBI status among persons recently exposed to TB, suggesting the potential for alternative markers to assess TBI status. Longitudinal analysis of these mediators during TPT is warranted to explore whether these markers can be used to assess likelihood of persistence of viable bacilli in Mtb-exposed individuals.</p><p><strong>Clinicaltrials: </strong>govID:NCT05621343.</p>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"151 ","pages":"102595"},"PeriodicalIF":2.8,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142915599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-19DOI: 10.1016/j.tube.2024.102596
Sabir Awad Mustafa
Purpose: Tuberculosis (TB) remains a significant public health concern globally. Bacille Calmette-Guérin (BCG) vaccination is widely used, but scar formation post-vaccination is not universal, which raises concerns about its efficacy. The Mantoux test is used to assess the immune response following BCG vaccination. This study aims to evaluate the prevalence of BCG scar formation among vaccinated children and its correlation with Mantoux test reactions.
Methods: This quantitative, cross-sectional descriptive study was conducted among children aged 3 months to 9 years at the vaccination office in Omdawanban, Sudan, from September to October 2021. Data were collected using structured surveys and the Mantoux skin test.
Results: Out of 350 vaccinated children, 285 (81.4 %) exhibited a visible BCG scar, while 65 (18.6 %) did not. Mantoux test positivity was observed in 132 children (37.7 %). A significant association was found between the presence of a BCG scar and a positive Mantoux test result (p < 0.05), with 39.3 % of children with a visible scar showing positive Mantoux results compared to 30.8 % of children without a scar. The likelihood of a positive Mantoux test was 3.2 times higher in children with a visible BCG scar (OR = 3.2, 95 % CI [1.8-5.8]). Mantoux positivity also varied by age, with the highest rate (41.2 %) observed among children aged 5-9 years (p = 0.03).
Conclusions: There is a significant association between BCG scar formation and Mantoux test positivity. Improved training for healthcare workers and better education for mothers about vaccination are recommended.
{"title":"Prevalence of BCG scar among vaccinated children and its correlation with Mantoux skin test at Omdawanban area, Sudan.","authors":"Sabir Awad Mustafa","doi":"10.1016/j.tube.2024.102596","DOIUrl":"https://doi.org/10.1016/j.tube.2024.102596","url":null,"abstract":"<p><strong>Purpose: </strong>Tuberculosis (TB) remains a significant public health concern globally. Bacille Calmette-Guérin (BCG) vaccination is widely used, but scar formation post-vaccination is not universal, which raises concerns about its efficacy. The Mantoux test is used to assess the immune response following BCG vaccination. This study aims to evaluate the prevalence of BCG scar formation among vaccinated children and its correlation with Mantoux test reactions.</p><p><strong>Methods: </strong>This quantitative, cross-sectional descriptive study was conducted among children aged 3 months to 9 years at the vaccination office in Omdawanban, Sudan, from September to October 2021. Data were collected using structured surveys and the Mantoux skin test.</p><p><strong>Results: </strong>Out of 350 vaccinated children, 285 (81.4 %) exhibited a visible BCG scar, while 65 (18.6 %) did not. Mantoux test positivity was observed in 132 children (37.7 %). A significant association was found between the presence of a BCG scar and a positive Mantoux test result (p < 0.05), with 39.3 % of children with a visible scar showing positive Mantoux results compared to 30.8 % of children without a scar. The likelihood of a positive Mantoux test was 3.2 times higher in children with a visible BCG scar (OR = 3.2, 95 % CI [1.8-5.8]). Mantoux positivity also varied by age, with the highest rate (41.2 %) observed among children aged 5-9 years (p = 0.03).</p><p><strong>Conclusions: </strong>There is a significant association between BCG scar formation and Mantoux test positivity. Improved training for healthcare workers and better education for mothers about vaccination are recommended.</p>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"151 ","pages":"102596"},"PeriodicalIF":2.8,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142915617","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-22DOI: 10.1016/j.tube.2024.102587
Berenice Villareal-Rivota , Yatsiri G. Meneses-Preza , Marcia Campillo-Navarro , Bibiana Patricia Ruiz-Sánchez , Rodolfo Soria-Castro , Jorge Barrios-Payán , Dulce Mata-Espinosa , Luis Donis-Maturano , Sonia M. Pérez-Tapia , Alma D. Chávez-Blanco , Sergio Estrada-Parra , Rogelio Hernández-Pando , Rommel Chacón-Salinas
Tuberculosis (TB) is a global health problem with diverse clinical manifestations. Different cells of the immune response participate in containing the infection, mainly through the development of granulomas. Mast cells (MCs) are hematopoietic cells that participate in the immune response to different pathogens, and in vitro evidence indicates that they can be activated by Mycobacterium tuberculosis (Mtb). The aim of this study was to evaluate the role of MCs in a murine TB model. We observed that KitW-sh/W−sh mast cell-deficient mice showed increased bacterial load in the lungs and the spleen compared to wild-type C57BL/6 mice. Furthermore, MC-deficient mice showed fewer pulmonary granulomas but an early higher inflammatory infiltrate. Interestingly, serum cytokine levels were altered in MC-deficient mice, which showed increased levels of IL-4, IL-5, and IL-22 during the early phase of the infection but increased levels of IFN-γ, IL-9, IL-10, and IL-21 during the late phase of the infection. These results show that mast cells play an important role during Mtb infection by modulating the immune response to the bacteria.
{"title":"Impaired control of Mycobacterium tuberculosis infection in mast cell-deficient KitW-sh/W−sh mice","authors":"Berenice Villareal-Rivota , Yatsiri G. Meneses-Preza , Marcia Campillo-Navarro , Bibiana Patricia Ruiz-Sánchez , Rodolfo Soria-Castro , Jorge Barrios-Payán , Dulce Mata-Espinosa , Luis Donis-Maturano , Sonia M. Pérez-Tapia , Alma D. Chávez-Blanco , Sergio Estrada-Parra , Rogelio Hernández-Pando , Rommel Chacón-Salinas","doi":"10.1016/j.tube.2024.102587","DOIUrl":"10.1016/j.tube.2024.102587","url":null,"abstract":"<div><div>Tuberculosis (TB) is a global health problem with diverse clinical manifestations. Different cells of the immune response participate in containing the infection, mainly through the development of granulomas. Mast cells (MCs) are hematopoietic cells that participate in the immune response to different pathogens, and <em>in vitro</em> evidence indicates that they can be activated by <em>Mycobacterium tuberculosis</em> (Mtb). The aim of this study was to evaluate the role of MCs in a murine TB model. We observed that Kit<sup>W-sh/W−sh</sup> mast cell-deficient mice showed increased bacterial load in the lungs and the spleen compared to wild-type C57BL/6 mice. Furthermore, MC-deficient mice showed fewer pulmonary granulomas but an early higher inflammatory infiltrate. Interestingly, serum cytokine levels were altered in MC-deficient mice, which showed increased levels of IL-4, IL-5, and IL-22 during the early phase of the infection but increased levels of IFN-γ, IL-9, IL-10, and IL-21 during the late phase of the infection. These results show that mast cells play an important role during Mtb infection by modulating the immune response to the bacteria.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"150 ","pages":"Article 102587"},"PeriodicalIF":2.8,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142745212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-19DOI: 10.1016/j.tube.2024.102579
Tianjun Liu , Jianzhou Meng , Bin Wang , Xiaohui Li , Qian Wang , Sihan Liu , Yan Guan , Xiao Wang , Yishuang Liu
Given the increasing prevalence of drug-resistant tuberculosis (TB), there is an urgent demand in developing novel anti-TB medications with highly effective, safe, and utilize innovative mechanisms of action. Blocking the mycolic acid synthesis pathway is well-established to be a significant strategy in developing anti-TB drugs, and Pks13 was identified as a crucial enzyme in this process. Importantly, the modes of action of recognized Pks13 inhibitors differ from traditional anti-TB medications, highlighting Pks13 as a potential and promising target in drug development within TB treatment. In this study, we discovered a compound named BMVC-8C3O that effectively inhibited the activity of Pks13 with a 6.94 μM IC50 value. The binding between BMVC-8C3O and Pks13 was validated through surface plasmon resonance (SPR) assay as well as molecular docking analysis. Moreover, the SPR assay showed that the mutation of Asn1640 and Ser1533 resulted in decreased affinity of BMVC-8C3O to Pks13. Additionally, BMVC-8C3O not only exhibited activity against Mycobacterium tuberculosis (MTB), but also displayed potential intracellular anti-TB activity in macrophages. In summary, our findings indicate that BMVC-8C3O holds great potential as a lead compound against TB.
{"title":"Identification of BMVC-8C3O as a novel Pks13 inhibitor with anti-tuberculosis activity","authors":"Tianjun Liu , Jianzhou Meng , Bin Wang , Xiaohui Li , Qian Wang , Sihan Liu , Yan Guan , Xiao Wang , Yishuang Liu","doi":"10.1016/j.tube.2024.102579","DOIUrl":"10.1016/j.tube.2024.102579","url":null,"abstract":"<div><div>Given the increasing prevalence of drug-resistant tuberculosis (TB), there is an urgent demand in developing novel anti-TB medications with highly effective, safe, and utilize innovative mechanisms of action. Blocking the mycolic acid synthesis pathway is well-established to be a significant strategy in developing anti-TB drugs, and Pks13 was identified as a crucial enzyme in this process. Importantly, the modes of action of recognized Pks13 inhibitors differ from traditional anti-TB medications, highlighting Pks13 as a potential and promising target in drug development within TB treatment. In this study, we discovered a compound named BMVC-8C3O that effectively inhibited the activity of Pks13 with a 6.94 μM IC<sub>50</sub> value. The binding between BMVC-8C3O and Pks13 was validated through surface plasmon resonance (SPR) assay as well as molecular docking analysis. Moreover, the SPR assay showed that the mutation of Asn1640 and Ser1533 resulted in decreased affinity of BMVC-8C3O to Pks13. Additionally, BMVC-8C3O not only exhibited activity against <em>Mycobacterium tuberculosis</em> (MTB), but also displayed potential intracellular anti-TB activity in macrophages. In summary, our findings indicate that BMVC-8C3O holds great potential as a lead compound against TB.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"150 ","pages":"Article 102579"},"PeriodicalIF":2.8,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142695830","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-13DOI: 10.1016/j.tube.2024.102577
Hua Zhang , Mengjiao Xue , Xinxin He , Lifang Sun , Qiang He , Yunguang Wang , Juan Jin
Background
Pulmonary tuberculosis (PTB) is the main cause of infection-related mortality and the most common infectious disease that develops resistance to antibiotics. Gut microbiota and their associated metabolites are assumed to induce and influence the development of PTB. However, the alterations of gut microbiota and metabolites in TB patients is currently unclear.
Methods
Fecal samples were collected from 13 PTB patients, 13 LTBI patients, and 13 healthy controls (HC). 16S rRNA sequencing and metabolomics were used to analyze the changes in the intestinal microbiota and the composition of fecal metabolites in groups.
Results
Our findings indicated that the α-diversity of the gut microbiota in patients with PTB and LTBI decreases compared to HC, and at the phylum level, the relative abundance of Firmicutes decreases and the relative abundance of Bacteroides increases. And six genera were notably enriched in PTB patients and four in LTBI patients. Metabolomic analysis showed alterations in metabolite levels, such as short-chain fatty acids and amino acids.
Conclusions
we comprehensively explored the changes in the gut microbes and fecal metabolites in patients with PTB and LTBI from the perspective of the gut microbiota, which may provide potential diagnostic biomarkers and therapeutic targets for TB diagnosis and treatment.
{"title":"Altered intestinal microbiota and fecal metabolites in patients with latent and active pulmonary tuberculosis","authors":"Hua Zhang , Mengjiao Xue , Xinxin He , Lifang Sun , Qiang He , Yunguang Wang , Juan Jin","doi":"10.1016/j.tube.2024.102577","DOIUrl":"10.1016/j.tube.2024.102577","url":null,"abstract":"<div><h3>Background</h3><div>Pulmonary tuberculosis (PTB) is the main cause of infection-related mortality and the most common infectious disease that develops resistance to antibiotics. Gut microbiota and their associated metabolites are assumed to induce and influence the development of PTB. However, the alterations of gut microbiota and metabolites in TB patients is currently unclear.</div></div><div><h3>Methods</h3><div>Fecal samples were collected from 13 PTB patients, 13 LTBI patients, and 13 healthy controls (HC). 16S rRNA sequencing and metabolomics were used to analyze the changes in the intestinal microbiota and the composition of fecal metabolites in groups.</div></div><div><h3>Results</h3><div>Our findings indicated that the α-diversity of the gut microbiota in patients with PTB and LTBI decreases compared to HC, and at the phylum level, the relative abundance of Firmicutes decreases and the relative abundance of Bacteroides increases. And six genera were notably enriched in PTB patients and four in LTBI patients. Metabolomic analysis showed alterations in metabolite levels, such as short-chain fatty acids and amino acids.</div></div><div><h3>Conclusions</h3><div>we comprehensively explored the changes in the gut microbes and fecal metabolites in patients with PTB and LTBI from the perspective of the gut microbiota, which may provide potential diagnostic biomarkers and therapeutic targets for TB diagnosis and treatment.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"149 ","pages":"Article 102577"},"PeriodicalIF":2.8,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142644841","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Several mycobacterial species are known to cause human diseases, such as tuberculosis and leprosy. In addition to these pathogenic species, there are also saprophytic representatives, which occasionally cause opportunistic infections. It is well established that numerous mycobacteria produce biofilms containing cellulose, and their genomes frequently harbor genes involved in cellulose degradation, such as celA1. Notably, the BCG Moreau vaccine strain carries a specific deletion of two-base pairs, resulting in a predicted protein with fewer than 100 amino acids in the catalytic portion at the C-terminal end. We investigated the functional consequences of this polymorphism and observed that recombinant enzyme from the Moreau strain lack catalytic activity. Furthermore, compared to the Pasteur strain, Moreau is unable to utilize carboxymethylcellulose (CMC) as the sole carbon source. These findings suggest an absence of cellulolytic activity in this strain, which may influence the bacterium virulence.
已知有几种分枝杆菌可导致人类疾病，如结核病和麻风病。除了这些致病菌外，还有一些吸附性分枝杆菌，它们偶尔也会引起机会性感染。众所周知，许多分枝杆菌会产生含有纤维素的生物膜，它们的基因组中经常含有参与纤维素降解的基因，如 celA1。值得注意的是，卡介苗莫罗菌株带有两个碱基对的特异性缺失，导致预测蛋白质 C 端催化部分的氨基酸少于 100 个。我们研究了这种多态性的功能性后果，发现莫罗菌株的重组酶缺乏催化活性。此外，与巴斯德菌株相比，莫罗菌株无法利用羧甲基纤维素（CMC）作为唯一的碳源。这些发现表明该菌株缺乏纤维素分解活性，这可能会影响细菌的毒力。
{"title":"Functional impact of a deletion in Mycobacterium bovis BCG Moreau celA1 gene","authors":"Leonardo Henrique Ferreira Gomes , Paloma Rezende Corrêa, Marcos Gustavo Araujo Schwarz, Leila Mendonça-Lima","doi":"10.1016/j.tube.2024.102576","DOIUrl":"10.1016/j.tube.2024.102576","url":null,"abstract":"<div><div>Several mycobacterial species are known to cause human diseases, such as tuberculosis and leprosy. In addition to these pathogenic species, there are also saprophytic representatives, which occasionally cause opportunistic infections. It is well established that numerous mycobacteria produce biofilms containing cellulose, and their genomes frequently harbor genes involved in cellulose degradation, such as <em>celA1</em>. Notably, the BCG Moreau vaccine strain carries a specific deletion of two-base pairs, resulting in a predicted protein with fewer than 100 amino acids in the catalytic portion at the C-terminal end. We investigated the functional consequences of this polymorphism and observed that recombinant enzyme from the Moreau strain lack catalytic activity. Furthermore, compared to the Pasteur strain, Moreau is unable to utilize carboxymethylcellulose (CMC) as the sole carbon source. These findings suggest an absence of cellulolytic activity in this strain, which may influence the bacterium virulence.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"149 ","pages":"Article 102576"},"PeriodicalIF":2.8,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142640034","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-08DOI: 10.1016/j.tube.2024.102575
Zhuo Quan , Yong Qiu , Meng Li , Fajun Tian , Rong Qu , Yi-Wei Tang , Xing-Hui Gao , Howard Takiff , Qian Gao
The sensitivity of Xpert MTB/RIF (Xpert) pooled testing is limited for diagnosing patients with paucibacillary tuberculosis (TB). We assessed whether pooled testing with Xpert MTB/RIF Ultra (Ultra) can be a sensitive and effective approach for mass TB screening. Conserved, frozen sputum samples, previously confirmed as positive or negative for Mycobacterium tuberculosis by individual Xpert assays, were mixed in pools of 4, 8, and 16 and then tested using Ultra. Each pool contained a single positive sample with varying mycobacterial loads. We then simulated TB screening at prevalence ranges of 0.2–1.0 % and calculated the cartridges required per case detected at different pool sizes. The overall sensitivity of Ultra pooled testing was high (88.9 %, 75.9–96.3). Sensitivity was greater in pools in which the positive sample had a high mycobacterial load compared to those with scant bacilli. As prevalence increased, the optimal pool size and benefits of pooled testing declined, but a pool size of 8 resulted in at least 80 % cartridge savings with the highest simulated prevalence. Sputum pooling using Ultra could be a sensitive and effective strategy for TB screening. However, broad TB screening in communities with limited resources will require new, lower-cost, high-throughput screening tools, perhaps based on non-sputum specimens.
{"title":"Pooling sputum samples for the Xpert MTB/RIF Ultra assay: A sensitive and effective screening strategy","authors":"Zhuo Quan , Yong Qiu , Meng Li , Fajun Tian , Rong Qu , Yi-Wei Tang , Xing-Hui Gao , Howard Takiff , Qian Gao","doi":"10.1016/j.tube.2024.102575","DOIUrl":"10.1016/j.tube.2024.102575","url":null,"abstract":"<div><div>The sensitivity of Xpert MTB/RIF (Xpert) pooled testing is limited for diagnosing patients with paucibacillary tuberculosis (TB). We assessed whether pooled testing with Xpert MTB/RIF Ultra (Ultra) can be a sensitive and effective approach for mass TB screening. Conserved, frozen sputum samples, previously confirmed as positive or negative for <em>Mycobacterium tuberculosis</em> by individual Xpert assays, were mixed in pools of 4, 8, and 16 and then tested using Ultra. Each pool contained a single positive sample with varying mycobacterial loads. We then simulated TB screening at prevalence ranges of 0.2–1.0 % and calculated the cartridges required per case detected at different pool sizes. The overall sensitivity of Ultra pooled testing was high (88.9 %, 75.9–96.3). Sensitivity was greater in pools in which the positive sample had a high mycobacterial load compared to those with scant bacilli. As prevalence increased, the optimal pool size and benefits of pooled testing declined, but a pool size of 8 resulted in at least 80 % cartridge savings with the highest simulated prevalence. Sputum pooling using Ultra could be a sensitive and effective strategy for TB screening. However, broad TB screening in communities with limited resources will require new, lower-cost, high-throughput screening tools, perhaps based on non-sputum specimens.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"149 ","pages":"Article 102575"},"PeriodicalIF":2.8,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142628875","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mycobacterium tuberculosis (MTB/Mtb) is the causative agent of tuberculosis (TB), a highly infectious serious airborne illness. TB usually affects the lungs, in 25 % of patients (children or immune impaired adults), mycobacteria can enter the blood stream and infect other bodily areas such the meninges, pleura, lymphatic system, genitourinary system, bones, and joints. Currently, the most challenging aspect of treating this illness is the ineffectiveness of the most potent first-line anti-TB medications, isoniazid, rifampin, pyrazinamide, and ethambutol, which can result in multidrug-resistant TB (MDR-TB), extensively drug-resistant TB (XDR-TB), and in rare instances, completely drug-resistant TB (TDR-TB). As a result, finding new pharmaceutical compounds to treat these diseases is a significant challenge for the scientific community. A number of bio-active molecules have been investigated in this quest, including quinoline, which is considered a promising candidate for the development of TB drugs. It is known that quinoline are low in toxicity and have a wide range of pharmacological properties. Researchers have investigated quinoline scaffolds as anti-TB drugs based on their biological spectrum. The objective of this review is to examine the recent development of quinoline and its structural characteristics crucial to its antitubercular (anti-TB) activity. A molecular analog of the TB treatment can be designed and identified with this information. As a result, future generation quinoline-based anti-TB agents with greater potency and safety can also be explored.
{"title":"Quinoline hybrid derivatives as effective structural motifs in the treatment of tuberculosis: Emphasis on structure-activity relationships","authors":"Venkatraman Hegde , Raveendra Madhukar Bhat , Srinivasa Budagumpi , Vinayak Adimule , Rangappa S. Keri","doi":"10.1016/j.tube.2024.102573","DOIUrl":"10.1016/j.tube.2024.102573","url":null,"abstract":"<div><div><em>Mycobacterium tuberculosis (MTB/Mtb)</em> is the causative agent of tuberculosis (TB), a highly infectious serious airborne illness. TB usually affects the lungs, in 25 % of patients (children or immune impaired adults), mycobacteria can enter the blood stream and infect other bodily areas such the meninges, pleura, lymphatic system, genitourinary system, bones, and joints. Currently, the most challenging aspect of treating this illness is the ineffectiveness of the most potent first-line anti-TB medications, isoniazid, rifampin, pyrazinamide, and ethambutol, which can result in multidrug-resistant TB (MDR-TB), extensively drug-resistant TB (XDR-TB), and in rare instances, completely drug-resistant TB (TDR-TB). As a result, finding new pharmaceutical compounds to treat these diseases is a significant challenge for the scientific community. A number of bio-active molecules have been investigated in this quest, including quinoline, which is considered a promising candidate for the development of TB drugs. It is known that quinoline are low in toxicity and have a wide range of pharmacological properties. Researchers have investigated quinoline scaffolds as anti-TB drugs based on their biological spectrum. The objective of this review is to examine the recent development of quinoline and its structural characteristics crucial to its antitubercular (anti-TB) activity. A molecular analog of the TB treatment can be designed and identified with this information. As a result, future generation quinoline-based anti-TB agents with greater potency and safety can also be explored.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"149 ","pages":"Article 102573"},"PeriodicalIF":2.8,"publicationDate":"2024-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142591358","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01DOI: 10.1016/j.tube.2024.102574
Federico Carlos Blanco , Cristina Lourdes Vázquez , Elizabeth Andrea García , Rosana Valeria Rocha , Laura Inés Klepp , Fabiana Bigi
A vaccine for bovine tuberculosis is urgently needed. The BCG vaccine (the Bacille Calmette-Guérin), currently the only licensed vaccine for tuberculosis in humans, offers variable protection in cattle. However, BCG is a highly safe vaccine, and any alternative vaccine must not only offer greater protection than BCG but also match and improve its safety profile. Mice are the most widely used animal models in tuberculosis research, particularly for pre-clinical vaccine evaluation. In these animal models, the key indicator of infection or vaccine efficacy is the mycobacteria load in the lungs. In this study, we evaluated the long-term protection conferred by vaccinating BALB/c mice with a Mycobacterium bovis triple mutant lacking the virulence genes phoP, esxA, and esxB. Our findings showed that the triple mutant protected the lungs of mice against M. bovis challenge for up to one-year post-vaccination. However, the bacterial load in the spleens predominantly comprised the vaccine strain, and the lungs also contained some of these bacteria. These results suggest that the vaccine strain persisted in the mouse organs for at least one year, which raised concerns about its potential safety for animal vaccination.
{"title":"Mycobacterium bovis mutant in the virulence factors PhoP, ESAT-6 and CFP-10 persisted in mouse organs after a year post-vaccination","authors":"Federico Carlos Blanco , Cristina Lourdes Vázquez , Elizabeth Andrea García , Rosana Valeria Rocha , Laura Inés Klepp , Fabiana Bigi","doi":"10.1016/j.tube.2024.102574","DOIUrl":"10.1016/j.tube.2024.102574","url":null,"abstract":"<div><div>A vaccine for bovine tuberculosis is urgently needed. The BCG vaccine (the Bacille Calmette-Guérin), currently the only licensed vaccine for tuberculosis in humans, offers variable protection in cattle. However, BCG is a highly safe vaccine, and any alternative vaccine must not only offer greater protection than BCG but also match and improve its safety profile. Mice are the most widely used animal models in tuberculosis research, particularly for pre-clinical vaccine evaluation. In these animal models, the key indicator of infection or vaccine efficacy is the mycobacteria load in the lungs. In this study, we evaluated the long-term protection conferred by vaccinating BALB/c mice with a <em>Mycobacterium bovis</em> triple mutant lacking the virulence genes <em>phoP</em>, <em>esxA</em>, and <em>esxB</em>. Our findings showed that the triple mutant protected the lungs of mice against <em>M. bovis</em> challenge for up to one-year post-vaccination. However, the bacterial load in the spleens predominantly comprised the vaccine strain, and the lungs also contained some of these bacteria. These results suggest that the vaccine strain persisted in the mouse organs for at least one year, which raised concerns about its potential safety for animal vaccination.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"149 ","pages":"Article 102574"},"PeriodicalIF":2.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142592540","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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