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}
Pub Date : 2024-10-23DOI: 10.1016/j.tube.2024.102572
Shanshan Wang , Xiao Xiao , Shulan Dong , Jiayi Cao , Sainan Wang , Haiyan Xiong , Xuliang Li , Ge Shao , Yi Hu , Xin Shen
Bedaquiline (BDQ) has shown efficacy in shortening treatment duration and enhancing treatment success rates for multidrug-resistant tuberculosis (MDR-TB), thereby prompting widespread adoption. However, resistance to BDQ has emerged. This study aimed to identify genetic characteristics associated with decreased susceptibility to BDQ, using a public database to aid in the detection of resistant strains. Seventy-one BDQ-resistant and 929 BDQ-susceptible isolates from the open-source CRyPTIC database were selected for analysis. Variant calling was conducted via the clockwork pipeline. Univariate logistic regression was performed for each gene mutation, followed by LASSO regression for further variant selection. Ultimately, a multiple linear regression model was developed using log2-transformed Minimum Inhibitory Concentration values as the dependent variable, with variant selection refined through stepwise regression based on the Akaike Information Criterion. Ten gene mutations were significantly associated with reduced BDQ susceptibility, including two key gene mutations: Rv0678_141_ins_1 and Rv1979c_D249E, with effect estimates of 1.76 (95 % CI: 0.67–2.84) and 1.69 (95 % CI: 0.22–3.17), respectively. Other implicated genes included Rv2699c_-84_del_1, hsaB_I179T, mmpL9_T241A, pncA_C14R, Rv0373c_G621S, Rv0893c_L27F, Rv1770_A4D, and Rv3428c_S327C. This study identified ten gene mutations linked to decreased susceptibility to BDQ, providing a reference for developing a comprehensive catalog of BDQ-resistant genes.
{"title":"Analysis of genetic characteristics associated with reduced bedaquiline susceptibility in multidrug-resistant Mycobacterium tuberculosis","authors":"Shanshan Wang , Xiao Xiao , Shulan Dong , Jiayi Cao , Sainan Wang , Haiyan Xiong , Xuliang Li , Ge Shao , Yi Hu , Xin Shen","doi":"10.1016/j.tube.2024.102572","DOIUrl":"10.1016/j.tube.2024.102572","url":null,"abstract":"<div><div>Bedaquiline (BDQ) has shown efficacy in shortening treatment duration and enhancing treatment success rates for multidrug-resistant tuberculosis (MDR-TB), thereby prompting widespread adoption. However, resistance to BDQ has emerged. This study aimed to identify genetic characteristics associated with decreased susceptibility to BDQ, using a public database to aid in the detection of resistant strains. Seventy-one BDQ-resistant and 929 BDQ-susceptible isolates from the open-source CRyPTIC database were selected for analysis. Variant calling was conducted via the clockwork pipeline. Univariate logistic regression was performed for each gene mutation, followed by LASSO regression for further variant selection. Ultimately, a multiple linear regression model was developed using log<sub>2</sub>-transformed Minimum Inhibitory Concentration values as the dependent variable, with variant selection refined through stepwise regression based on the Akaike Information Criterion. Ten gene mutations were significantly associated with reduced BDQ susceptibility, including two key gene mutations: <em>Rv0678</em>_141_ins_1 and <em>Rv1979c</em>_D249E, with effect estimates of 1.76 (95 % CI: 0.67–2.84) and 1.69 (95 % CI: 0.22–3.17), respectively. Other implicated genes included <em>Rv2699c</em>_-84_del_1, <em>hsaB</em>_I179T, <em>mmpL9</em>_T241A, <em>pncA</em>_C14R, <em>Rv0373c</em>_G621S, <em>Rv0893c</em>_L27F, <em>Rv1770</em>_A4D, and <em>Rv3428c</em>_S327C. This study identified ten gene mutations linked to decreased susceptibility to BDQ, providing a reference for developing a comprehensive catalog of BDQ-resistant genes.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"149 ","pages":"Article 102572"},"PeriodicalIF":2.8,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142587296","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}
Host-directed therapies (HDT) via modulation of specific host responses like inflammation can limit mycobacterial infection. HDTs could be included in current TB therapy as an adjunct to increase bacterial clearance and limit tissue damage to control spread. Individually, Mycobacterium indicus pranii (MIP) and human beta defensin-2 (hBD-2) are promising therapies for tuberculosis (TB). They can directly target the TB bacilli and enhance cell-mediated immune responses, which is limiting with conventional drugs. Therefore, our study investigated the combined application of MIP and hBD-2 to evaluate their efficacy in clearing infections caused by Mycobacterium smegmatis (M.smeg) and Mycobacterium tuberculosis (M.tb) (both avirulent; H37Ra and virulent strain; H37Rv) in THP-1 cells and human monocyte-derived macrophages (MDMs). A strong pro-inflammatory response was observed against the combination of MIP and hBD-2 which also correlated with a significant reduction in the bacterial load. This combination further showed protection against M.tb by enhancing pyroptosis in the infected cells. The study suggests the combined use of these potent immunomodulators, which could be employed as an effective mode of therapy as adjuvants against mycobacterial infections after validation in a suitable animal model.
{"title":"Synergistic role of Mycobacterium indicus pranii and human beta Defensin-2 as adjunctive therapy against Mycobacterium tuberculosis","authors":"Shah Faisal , Deepak Vats , Sudhasini Panda , Vidushi Sharma , Kalpana Luthra , Anant Mohan , Savita Kulkarni , Pramod Kumar Gupta , Archana Singh","doi":"10.1016/j.tube.2024.102571","DOIUrl":"10.1016/j.tube.2024.102571","url":null,"abstract":"<div><div>Host-directed therapies (HDT) via modulation of specific host responses like inflammation can limit mycobacterial infection. HDTs could be included in current TB therapy as an adjunct to increase bacterial clearance and limit tissue damage to control spread. Individually, <em>Mycobacterium indicus pranii (MIP)</em> and human beta defensin-2 (hBD-2) are promising therapies for tuberculosis (TB). They can directly target the TB bacilli and enhance cell-mediated immune responses, which is limiting with conventional drugs. Therefore, our study investigated the combined application of MIP and hBD-2 to evaluate their efficacy in clearing infections caused by <em>Mycobacterium smegmatis</em> (<em>M.</em><em>smeg</em>) and <em>Mycobacterium tuberculosis (M</em>.<em>tb)</em> (both avirulent; H37Ra and virulent strain; H37Rv) in THP-1 cells and human monocyte-derived macrophages (MDMs). A strong pro-inflammatory response was observed against the combination of MIP and hBD-2 which also correlated with a significant reduction in the bacterial load. This combination further showed protection against <em>M.tb</em> by enhancing pyroptosis in the infected cells. The study suggests the combined use of these potent immunomodulators, which could be employed as an effective mode of therapy as adjuvants against mycobacterial infections after validation in a suitable animal model.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"149 ","pages":"Article 102571"},"PeriodicalIF":2.8,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142508880","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 : 2024-10-11DOI: 10.1016/j.tube.2024.102570
Shoupeng Ding , Xiaomei Yi , Jinghua Gao , Chunxiao Huang , Yuyang Zhou , Yimei Yang , Zihan Cai
Objective
The asymptomatic nature of tuberculosis (TB) during its latent phase, combined with limitations in current diagnostic methods, makes accurate diagnosis challenging. This study aims to identify TB diagnostic biomarkers by integrating gene expression screening with machine learning, evaluating their diagnostic potential and correlation with immune cell infiltration.
Methods
We analyzed GSE19435, GSE19444, and GSE54992 datasets to identify differentially expressed genes (DEGs). GO and KEGG enrichment characterized gene functions. Three machine learning algorithms identified potential biomarkers, validated with GSE83456, GSE62525, and RT-qPCR on clinical samples. Immune cell infiltration was analyzed and verified with blood data.
Results
249 DEGs were identified, with PDE7A and DOK3 emerging as potential biomarkers. RT-qPCR confirmed their expression, showing AUCs above 0.75 and a combined AUC of 0.926 for TB diagnosis. Immune infiltration analysis revealed strong correlations between PDE7A, DOK3, and immune cells.
Conclusion
PDE7A and DOK3 show strong diagnostic potential for TB, closely linked to immune cell infiltration, and may serve as promising biomarkers and therapeutic targets.
{"title":"Combining bioinformatics and machine learning to identify diagnostic biomarkers of TB associated with immune cell infiltration","authors":"Shoupeng Ding , Xiaomei Yi , Jinghua Gao , Chunxiao Huang , Yuyang Zhou , Yimei Yang , Zihan Cai","doi":"10.1016/j.tube.2024.102570","DOIUrl":"10.1016/j.tube.2024.102570","url":null,"abstract":"<div><h3>Objective</h3><div>The asymptomatic nature of tuberculosis (TB) during its latent phase, combined with limitations in current diagnostic methods, makes accurate diagnosis challenging. This study aims to identify TB diagnostic biomarkers by integrating gene expression screening with machine learning, evaluating their diagnostic potential and correlation with immune cell infiltration.</div></div><div><h3>Methods</h3><div>We analyzed GSE19435, GSE19444, and GSE54992 datasets to identify differentially expressed genes (DEGs). GO and KEGG enrichment characterized gene functions. Three machine learning algorithms identified potential biomarkers, validated with GSE83456, GSE62525, and RT-qPCR on clinical samples. Immune cell infiltration was analyzed and verified with blood data.</div></div><div><h3>Results</h3><div>249 DEGs were identified, with PDE7A and DOK3 emerging as potential biomarkers. RT-qPCR confirmed their expression, showing AUCs above 0.75 and a combined AUC of 0.926 for TB diagnosis. Immune infiltration analysis revealed strong correlations between PDE7A, DOK3, and immune cells.</div></div><div><h3>Conclusion</h3><div>PDE7A and DOK3 show strong diagnostic potential for TB, closely linked to immune cell infiltration, and may serve as promising biomarkers and therapeutic targets.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"149 ","pages":"Article 102570"},"PeriodicalIF":2.8,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142442504","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 is a deadly pathogen that claims millions of lives every year. Current research focuses on finding new anti-tuberculosis drugs that are safe and effective, with lesser side effects and toxicity. One important approach is to identify bio-enhancers that can improve the effectiveness of anti-tuberculosis drugs, resulting in reduced doses and shortened treatment times. The present study investigates the use of C-4 modified isotetrones as bio-enhancers. A series of studies suggest an isotetrone, labeled as C11, inhibits growth, improves MIC, MBC and enhances the killing of M. tuberculosis H37Rv strain when used in combination with the first line and injectable anti-TB drugs in a dose-dependent manner. The combination of C11 and rifampicin also reduces the generation of spontaneous mutants against rifampicin and reaches a mutation prevention concentration (MPC) with moderate rifampicin concentrations. The identified compounds are effective against the MDR strain of M. tuberculosis and non-cytotoxic in HepG2 cells. We find that C11 induces the generation of reactive oxygen species (ROS) inside macrophages and within bacteria, resulting in better efficacy.
{"title":"A novel C-4-modified isotetrone acts as a potent bio-enhancer to augment the activities of anti-tuberculosis drugs against Mycobacterium tuberculosis","authors":"Naveen Prakash Bokolia , Kingshuk Bag , Biplab Sarkar , Ruchi Jhawar , Dipankar Chatterji , Narayanaswamy Jayaraman , Anirban Ghosh","doi":"10.1016/j.tube.2024.102569","DOIUrl":"10.1016/j.tube.2024.102569","url":null,"abstract":"<div><div><em>Mycobacterium tuberculosis</em> is a deadly pathogen that claims millions of lives every year. Current research focuses on finding new anti-tuberculosis drugs that are safe and effective, with lesser side effects and toxicity. One important approach is to identify bio-enhancers that can improve the effectiveness of anti-tuberculosis drugs, resulting in reduced doses and shortened treatment times. The present study investigates the use of <em>C</em>-4 modified isotetrones as bio-enhancers. A series of studies suggest an isotetrone, labeled as C11, inhibits growth, improves MIC, MBC and enhances the killing of <em>M. tuberculosis</em> H37Rv strain when used in combination with the first line and injectable anti-TB drugs in a dose-dependent manner. The combination of C11 and rifampicin also reduces the generation of spontaneous mutants against rifampicin and reaches a mutation prevention concentration (MPC) with moderate rifampicin concentrations. The identified compounds are effective against the MDR strain of <em>M. tuberculosis</em> and non-cytotoxic in HepG2 cells. We find that C11 induces the generation of reactive oxygen species (ROS) inside macrophages and within bacteria, resulting in better efficacy.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"149 ","pages":"Article 102569"},"PeriodicalIF":2.8,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142366685","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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