Pub Date : 2025-03-26DOI: 10.1016/j.tube.2025.102635
Xiaochun Wang , Yun Xu , Qiangsen Zhong , Zian Zhang , LingYun Kong , Mingming Zhou , Runlin Wang , Xinxin Pi , Suwen Qiao
Mycobacterium tuberculosis (M. tb) serves as the main pathogen responsible for Tuberculosis (TB). It predominantly targets the lungs and leads to a persistent infectious disease. The spread of drug-resistant tuberculosis and the exacerbation of economic burdens due to co-infections with Human Immunodeficiency Virus (HIV)/M. tb pose significant challenges in prevention and treatment. The BCG vaccine is currently the only approved (TB) vaccine, but its protective effect is limited for adults. In this research, we engineered the fusion protein gene RPC4, incorporating four crucial antigens from M. tb. The study revealed that the IFN-γ levels in the peripheral blood of infected patients significantly surpassed those in healthy individuals. To assess the immune response of RPC4 as a BCG-enhanced vaccine following initial immunity, researchers administered it alongside the novel adjuvant DIMQ to immunize mice. Experiments revealed that the BCG + RPC4/DIMQ vaccine induces a substantial immunogenic response in the mice.
{"title":"Construction and expression of multi-stage antigen fusion protein RPC4 vaccine for Mycobacterium tuberculosis and its immunogenicity analysis in combination with adjuvant DIMQ","authors":"Xiaochun Wang , Yun Xu , Qiangsen Zhong , Zian Zhang , LingYun Kong , Mingming Zhou , Runlin Wang , Xinxin Pi , Suwen Qiao","doi":"10.1016/j.tube.2025.102635","DOIUrl":"10.1016/j.tube.2025.102635","url":null,"abstract":"<div><div><em>Mycobacterium tuberculosis</em> (<em>M. tb</em>) serves as the main pathogen responsible for Tuberculosis (TB). It predominantly targets the lungs and leads to a persistent infectious disease. The spread of drug-resistant tuberculosis and the exacerbation of economic burdens due to co-infections with Human Immunodeficiency Virus (HIV)/<em>M. tb</em> pose significant challenges in prevention and treatment. The BCG vaccine is currently the only approved (TB) vaccine, but its protective effect is limited for adults. In this research, we engineered the fusion protein gene RPC4, incorporating four crucial antigens from <em>M. tb</em>. The study revealed that the IFN-γ levels in the peripheral blood of infected patients significantly surpassed those in healthy individuals. To assess the immune response of RPC4 as a BCG-enhanced vaccine following initial immunity, researchers administered it alongside the novel adjuvant DIMQ to immunize mice. Experiments revealed that the BCG + RPC4/DIMQ vaccine induces a substantial immunogenic response in the mice.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"152 ","pages":"Article 102635"},"PeriodicalIF":2.8,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143738964","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}
Previously, a slot blot or an indirect enzyme-linked immunosorbent assay (ELISA) using a synthetic or purified MTP antigen, conceptually demonstrated IgG antibody induction in pulmonary TB patients, albeit with small sample sizes and differing sensitivity. Therefore, we evaluated an IgG MTP ELISA in larger populations from The Gambia (n = 549), Uganda (n = 161), and South Africa (n = 193), comprising human immunodeficiency virus (HIV) positive and negative, with microbiologically confirmed active TB. The association between the IgG level and demographic characteristics was determined by multivariate logistic regression. The sensitivity (44.8–61.2 %) and specificity (33.4–78.5 %) varied in the three cohorts. Anti-MTP antibody titres differed between the TB positive and negative groups within the South African and The Gambian cohorts (p < 0.001), but not in Uganda (p = 0.35). Antibodies were detected in HIV positive and negative patients and were reduced at 6-month follow-up after treatment (p > 0.067). The study verified previous findings that anti-MTP antibodies, and therefore MTP antigen, are produced during active TB. However, the accuracy of the MTP-IgG ELISA was low, and is therefore not suitable as a target product profile in the high burden TB areas investigated. Further studies are needed to clarify the variable reactivities in different geographical areas.
{"title":"IgG antibody response to Mycobacterium tuberculosis curli pili (MTP) in people from different geographical regions in Sub-Saharan Africa","authors":"Koobashnee Pillay , Theresa Coetzer , Catherine Connolly , Balakrishna Pillay , Thamsanqa Chiliza , Kogieleum Naidoo , Jayne Sutherland , Thumbi Ndung'u , Harriet Mayanja-Kizza , Manormoney Pillay","doi":"10.1016/j.tube.2025.102634","DOIUrl":"10.1016/j.tube.2025.102634","url":null,"abstract":"<div><div>Previously, a slot blot or an indirect enzyme-linked immunosorbent assay (ELISA) using a synthetic or purified MTP antigen, conceptually demonstrated IgG antibody induction in pulmonary TB patients, albeit with small sample sizes and differing sensitivity. Therefore, we evaluated an IgG MTP ELISA in larger populations from The Gambia (n = 549), Uganda (n = 161), and South Africa (n = 193), comprising human immunodeficiency virus (HIV) positive and negative, with microbiologically confirmed active TB. The association between the IgG level and demographic characteristics was determined by multivariate logistic regression. The sensitivity (44.8–61.2 %) and specificity (33.4–78.5 %) varied in the three cohorts. Anti-MTP antibody titres differed between the TB positive and negative groups within the South African and The Gambian cohorts (p < 0.001), but not in Uganda (p = 0.35). Antibodies were detected in HIV positive and negative patients and were reduced at 6-month follow-up after treatment (p > 0.067). The study verified previous findings that anti-MTP antibodies, and therefore MTP antigen, are produced during active TB. However, the accuracy of the MTP-IgG ELISA was low, and is therefore not suitable as a target product profile in the high burden TB areas investigated. Further studies are needed to clarify the variable reactivities in different geographical areas.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"152 ","pages":"Article 102634"},"PeriodicalIF":2.8,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143714208","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-15DOI: 10.1016/j.tube.2025.102633
Godlove T. Chaula , Lucy Namkinga , Ally Mahadhy , Wilber Sabiiti , Nyanda Elias Ntinginya , Bariki Mtafya
Background
We assessed the impact of centrifugation on recovery of Mycobacterium tuberculosis (M.tb).
Methods
We used 0.5 McFarland from the 2 weeks M. tb, H37Rv culture and homogenized sputum for our experiments. Samples were decontaminated by 2 % NaOH for 20 min and with PBS for controls. Decontaminated aliquots were centrifuged at 2000×g, 3000×g and 6000×g for 40 min and inoculated on MGIT and LJ media. MGITs were incubated into the BACTEC MGIT 960 Systems following BD manuals and data analyzed on GraphPad Software.
Results
The positivity (days) for M. tb, H37Rv in MGIT and LJ decreased from 20.4 to 17.7 and from 47.6 to 26.6 at 2000×g and 6000×g, respectively; P > 0.05. For controls, MGIT and LJ positivity (days) decreased from 19 to 10 and from 39.2 to 11.2 at 2000×g and 6000×g, respectively; P > 0.05. MGIT positivity was 6(60 %) at 2000×g and 8(80 %) at 6000×g, corresponding to mean (±SD) of 13.7 ± 6.7 and 9.06 ± 4.6 days, respectively for sputum. LJ positivity was 1(10 %) at 2000×g and 7(70 %) at 6000×g. MGIT contamination for controls (sputum) was over 50 % and 80 % for LJ.
Conclusion
Higher centrifugation speed improves yield and sensitivity of TB culture.
{"title":"High centrifugation speed improves recovery of M. tuberculosis and yield of culture","authors":"Godlove T. Chaula , Lucy Namkinga , Ally Mahadhy , Wilber Sabiiti , Nyanda Elias Ntinginya , Bariki Mtafya","doi":"10.1016/j.tube.2025.102633","DOIUrl":"10.1016/j.tube.2025.102633","url":null,"abstract":"<div><h3>Background</h3><div>We assessed the impact of centrifugation on recovery of <em>Mycobacterium tuberculosis</em> (<em>M.tb</em>).</div></div><div><h3>Methods</h3><div>We used 0.5 McFarland from the 2 weeks <em>M. tb,</em> H37Rv culture and homogenized sputum for our experiments. Samples were decontaminated by 2 % NaOH for 20 min and with PBS for controls. Decontaminated aliquots were centrifuged at 2000×<em>g</em>, 3000×<em>g</em> and 6000×<em>g</em> for 40 min and inoculated on MGIT and LJ media. MGITs were incubated into the BACTEC MGIT 960 Systems following BD manuals and data analyzed on GraphPad Software.</div></div><div><h3>Results</h3><div>The positivity (days) for <em>M. tb</em>, <em>H37Rv</em> in MGIT and LJ decreased from 20.4 to 17.7 and from 47.6 to 26.6 at 2000×<em>g</em> and 6000×<em>g</em>, respectively; P > 0.05. For controls, MGIT and LJ positivity (days) decreased from 19 to 10 and from 39.2 to 11.2 at 2000×<em>g</em> and 6000×<em>g</em>, respectively; P > 0.05. MGIT positivity was 6(60 %) at 2000×<em>g</em> and 8(80 %) at 6000×<em>g</em>, corresponding to mean (±SD) of 13.7 ± 6.7 and 9.06 ± 4.6 days, respectively for sputum. LJ positivity was 1(10 %) at 2000×<em>g</em> and 7(70 %) at 6000×<em>g</em>. MGIT contamination for controls (sputum) was over 50 % and 80 % for LJ.</div></div><div><h3>Conclusion</h3><div>Higher centrifugation speed improves yield and sensitivity of TB culture.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"152 ","pages":"Article 102633"},"PeriodicalIF":2.8,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143706412","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 : 2025-03-14DOI: 10.1016/j.tube.2025.102630
Seungmo Kim , Seung Heon Lee , Gisu Kang , Gyeong In Lee , Hyeon-Su Kim , Jeong Seong Yang , Youngsuk Park , Byoung Oh Hwang , Hyejin Kim
The connection between genetic mutations linked to delamanid resistance and phenotypic resistance remains unclear. We assessed the phenotypic effects of delamanid-resistant mutations in the Mycobacterium tuberculosis H37Rv strain through gene disruption using homologous recombination and complementation tests. Delamanid resistance was assessed by determining the minimum inhibitory concentration (MIC) via the 7H9 microdilution method. Sanger sequencing identified mutations, and conservation of the mutated residues was predicted through multiple sequence alignments of orthologs. A total of 116 isolates with MIC ≥0.025 μg/mL were analyzed, among which mutations were identified in the ddn and fbiA genes. Isogenic strains were generated based on these mutations. The ddn or fbiA isogenic strains with Ala77Val, Gly81Ser, Asn25fs, and Leu104Phe in fbiA had MICs ≥0.8 μg/mL, indicating resistance. In contrast, the ddn isogenic strain with Pro12Ala had an MIC of 0.012 μg/mL, showing susceptibility, while Gly96Asp in fbiA had an MIC of 0.1 μg/mL, indicating resistance. All mutations, except for Pro12Ala, were conserved in the protein sequences of both FbiA and Ddn and their mycobacterial orthologs. The characterization of these mutations provides insights into the mechanisms of delamanid resistance, which may inform the development of optimized treatment strategies.
{"title":"Functional analysis of genetic mutations in ddn and fbiA linked to delamanid resistance in rifampicin-resistant Mycobacterium tuberculosis","authors":"Seungmo Kim , Seung Heon Lee , Gisu Kang , Gyeong In Lee , Hyeon-Su Kim , Jeong Seong Yang , Youngsuk Park , Byoung Oh Hwang , Hyejin Kim","doi":"10.1016/j.tube.2025.102630","DOIUrl":"10.1016/j.tube.2025.102630","url":null,"abstract":"<div><div>The connection between genetic mutations linked to delamanid resistance and phenotypic resistance remains unclear. We assessed the phenotypic effects of delamanid-resistant mutations in the <em>Mycobacterium tuberculosis</em> H37Rv strain through gene disruption using homologous recombination and complementation tests. Delamanid resistance was assessed by determining the minimum inhibitory concentration (MIC) via the 7H9 microdilution method. Sanger sequencing identified mutations, and conservation of the mutated residues was predicted through multiple sequence alignments of orthologs. A total of 116 isolates with MIC ≥0.025 μg/mL were analyzed, among which mutations were identified in the <em>ddn</em> and <em>fbiA</em> genes. Isogenic strains were generated based on these mutations. The <em>ddn</em> or <em>fbiA</em> isogenic strains with Ala77Val, Gly81Ser, Asn25fs, and Leu104Phe in <em>fbiA</em> had MICs ≥0.8 μg/mL, indicating resistance. In contrast, the <em>ddn</em> isogenic strain with Pro12Ala had an MIC of 0.012 μg/mL, showing susceptibility, while Gly96Asp in <em>fbiA</em> had an MIC of 0.1 μg/mL, indicating resistance. All mutations, except for Pro12Ala, were conserved in the protein sequences of both FbiA and Ddn and their mycobacterial orthologs. The characterization of these mutations provides insights into the mechanisms of delamanid resistance, which may inform the development of optimized treatment strategies.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"152 ","pages":"Article 102630"},"PeriodicalIF":2.8,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143680656","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 : 2025-03-12DOI: 10.1016/j.tube.2025.102632
Ágota Madai , Marcos De Andrés Montero , Luca Kis , Csaba Szalontai , Anna Szigeti , István Major , Attila Kiss P. , Olga Spekker
The aim of our paper is to demonstrate a case (KD429) with tuberculous meningitis (TBM) from the 2nd–3rd‒century‒CE Carpathian Basin. The skeleton of KD429 was subject to a detailed macromorphological evaluation, focusing on the detection of pathological lesions likely related to tuberculosis (TB). It was the presence of endocranial alterations, especially the TB-specific granular impressions, based on which the diagnosis of TBM was established in KD429. Besides KD429, only eight cases with TB have been published from the Sarmatian-period (1st–5th centuries CE) Carpathian Basin. Reports of archaeological cases with TB, like KD429, can provide invaluable information about the spatio-temporal distribution of the disease in the past. Nonetheless, to get a more accurate picture about the burden that TB may have put on the Sarmatians, the systematic macromorphological (re-)evaluation of their osteoarchaeological series would be advantageous. Interestingly, the skeleton of KD429 was unearthed from not a grave-pit but a storage pit from the archaeological site of Kiskundorozsma–Daruhalom-dűlő II (Hungary). At the current state of research, the motive behind the exclusion of KD429 from the “normal” burial custom cannot be determined; therefore, it remains an open question whether their disease (TBM) played a role in it or not.
{"title":"Chasing the “White Plague” in the Barbaricum of the Carpathian Basin – A case with tuberculous meningitis discovered in a Sarmatian-period (2nd–3rd-century-CE) storage pit from the archaeological site of Kiskundorozsma–Daruhalom-dűlő II (Hungary)","authors":"Ágota Madai , Marcos De Andrés Montero , Luca Kis , Csaba Szalontai , Anna Szigeti , István Major , Attila Kiss P. , Olga Spekker","doi":"10.1016/j.tube.2025.102632","DOIUrl":"10.1016/j.tube.2025.102632","url":null,"abstract":"<div><div>The aim of our paper is to demonstrate a case (<strong>KD429</strong>) with tuberculous meningitis (TBM) from the 2nd–3rd‒century‒CE Carpathian Basin. The skeleton of <strong>KD429</strong> was subject to a detailed macromorphological evaluation, focusing on the detection of pathological lesions likely related to tuberculosis (TB). It was the presence of endocranial alterations, especially the TB-specific granular impressions, based on which the diagnosis of TBM was established in <strong>KD429</strong>. Besides <strong>KD429</strong>, only eight cases with TB have been published from the Sarmatian-period (1st–5th centuries CE) Carpathian Basin. Reports of archaeological cases with TB, like <strong>KD429</strong>, can provide invaluable information about the spatio-temporal distribution of the disease in the past. Nonetheless, to get a more accurate picture about the burden that TB may have put on the Sarmatians, the systematic macromorphological (re-)evaluation of their osteoarchaeological series would be advantageous. Interestingly, the skeleton of <strong>KD429</strong> was unearthed from not a grave-pit but a storage pit from the archaeological site of Kiskundorozsma–Daruhalom-dűlő II (Hungary). At the current state of research, the motive behind the exclusion of <strong>KD429</strong> from the “normal” burial custom cannot be determined; therefore, it remains an open question whether their disease (TBM) played a role in it or not.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"152 ","pages":"Article 102632"},"PeriodicalIF":2.8,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143628521","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Inhaled therapy of tuberculosis (TB) by a Dry Powder Inhalation (DPI) comprising mycobacteriophage D29 and TM4 was non-inferior to oral anti-tuberculosis therapy (ATT) with isoniazid and rifampicin in a mouse model of infection with Mycobacterium tuberculosis (Mtb). No pharmaceutical phage product of mycobacteriophages is approved for large-scale production. We scaled up preparation and downstream processing of phages, developed DPI formulations, and established methods for determining identity, purity, assay, stability, and critical quality attributes (CQA). We carried out cell-based assays of intracellular bactericidal activity and pharmacokinetics and comparative efficacy in Mtb-infected mice. Daily doses of the DPI containing ∼1010 Plaque Forming Units/dose DPI reduced Mtb colony forming units (CFU) in the lungs from 6.4 ± 0.3-log to 4.8 ± 0.7-log in four weeks, while oral human equivalent doses (HED) of isoniazid and rifampicin reduced CFU to 3.8 ± 0.8-log. Combining inhaled phages with oral drugs sterilized the lungs of one of four mice and reduced group mean CFU to 2.3-log. Inhalations significantly upregulated tumor necrosis factor (TNF) in lung tissue to ∼1500 pg/ml of homogenate, improved organ morphology, and reduced histopathology. The HD DPI may be a useful adjunct to oral drugs. Dose-finding animal efficacy studies are required before assessing preclinical safety.
{"title":"Dry powder Inhalation of lytic mycobacteriophages for adjunct therapy in a mouse model of infection with Mycobacterium tuberculosis","authors":"Sunil K. Raman , Trisha Roy , Khushboo Verma , Chunna Yadav , Sonia Verma , Venkata Siva Reddy Deivreddy , Hasham Shafi Sofi , Reena Bharti , Rahul Sharma , Himanshu Bansode , Akhilesh Kumar , Rakesh Kumar Sharma , Jyotsna Singh , Madhav N. Mugale , Urmi Bajpai , Vikas Jain , Amit Kumar Singh , Amit Misra","doi":"10.1016/j.tube.2025.102631","DOIUrl":"10.1016/j.tube.2025.102631","url":null,"abstract":"<div><div>Inhaled therapy of tuberculosis (TB) by a Dry Powder Inhalation (DPI) comprising mycobacteriophage D29 and TM4 was non-inferior to oral anti-tuberculosis therapy (ATT) with isoniazid and rifampicin in a mouse model of infection with <em>Mycobacterium tuberculosis</em> (Mtb). No pharmaceutical phage product of mycobacteriophages is approved for large-scale production. We scaled up preparation and downstream processing of phages, developed DPI formulations, and established methods for determining identity, purity, assay, stability, and critical quality attributes (CQA). We carried out cell-based assays of intracellular bactericidal activity and pharmacokinetics and comparative efficacy in Mtb-infected mice. Daily doses of the DPI containing ∼10<sup>10</sup> Plaque Forming Units/dose DPI reduced Mtb colony forming units (CFU) in the lungs from 6.4 ± 0.3-log to 4.8 ± 0.7-log in four weeks, while oral human equivalent doses (HED) of isoniazid and rifampicin reduced CFU to 3.8 ± 0.8-log. Combining inhaled phages with oral drugs sterilized the lungs of one of four mice and reduced group mean CFU to 2.3-log. Inhalations significantly upregulated tumor necrosis factor (TNF) in lung tissue to ∼1500 pg/ml of homogenate, improved organ morphology, and reduced histopathology. The HD DPI may be a useful adjunct to oral drugs. Dose-finding animal efficacy studies are required before assessing preclinical safety.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"152 ","pages":"Article 102631"},"PeriodicalIF":2.8,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143628522","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 : 2025-03-07DOI: 10.1016/j.tube.2025.102627
B. Jolly , J. Saad , A. Farra , A. Manirakiza , G. Zandanga , E. Nakoune , Y. Boum II , E. Gando , G. Grine , C. Mossoro-Kpinde , M. Drancourt
Tuberculosis, a significant public health concern in Central African Republic lacks whole-genome-based identification and typing of the Mycobacterium tuberculosis complex strains circulating in populations in that country. Here, we investigated 68 rifampin-resistant clinical isolates collected in 2024 from eight districts in Bangui and surrounding regions. The analysis revealed that all isolates were M. tuberculosis stricto sensu, distributed across nine lineages: L4.1.2.1 Haarlem (n = 20), L4.6 Euro-American (n = 17), L4.6.1.2 Uganda (n = 13), L4.6.2.2 Cameroon (n = 12), and L4.1.1.1 X-Type (n = 2), and single isolates in L4.1 (Euro-American), L4.6.1 (Uganda), L4.3.1 (LAM), and L3 (Delhi-CAS). The antibiotic resistance profile showed that 9/68 (13.2 %) of the M. tuberculosis isolates were susceptible, while 59/68 (86.7 %) exhibited at least one predicted antibiotic resistance. These data provide new insights into tuberculosis transmission in Central African Republic in contrast to reports from neighboring countries, including the absence of Mycobacterium bovis, hence zoonotic tuberculosis and other factors. This preliminary study limited to rifampin-resistant isolates, nevertheless paves the way for a genome-based survey of tuberculosis in Central African Republic which is essential for enhancing the management and control of the deadly tuberculosis that is a public health concern in the country.
{"title":"A snapshot of genomic diversity and transmission clusters of rifampin-resistant Mycobacterium tuberculosis complex in the Central African Republic","authors":"B. Jolly , J. Saad , A. Farra , A. Manirakiza , G. Zandanga , E. Nakoune , Y. Boum II , E. Gando , G. Grine , C. Mossoro-Kpinde , M. Drancourt","doi":"10.1016/j.tube.2025.102627","DOIUrl":"10.1016/j.tube.2025.102627","url":null,"abstract":"<div><div>Tuberculosis, a significant public health concern in Central African Republic lacks whole-genome-based identification and typing of the <em>Mycobacterium tuberculosis</em> complex strains circulating in populations in that country. Here, we investigated 68 rifampin-resistant clinical isolates collected in 2024 from eight districts in Bangui and surrounding regions. The analysis revealed that all isolates were <em>M. tuberculosis stricto sensu</em>, distributed across nine lineages: L4.1.2.1 Haarlem (n = 20), L4.6 Euro-American (n = 17), L4.6.1.2 Uganda (n = 13), L4.6.2.2 Cameroon (n = 12), and L4.1.1.1 X-Type (n = 2), and single isolates in L4.1 (Euro-American), L4.6.1 (Uganda), L4.3.1 (LAM), and L3 (Delhi-CAS). The antibiotic resistance profile showed that 9/68 (13.2 %) of the <em>M. tuberculosis</em> isolates were susceptible, while 59/68 (86.7 %) exhibited at least one predicted antibiotic resistance. These data provide new insights into tuberculosis transmission in Central African Republic in contrast to reports from neighboring countries, including the absence of <em>Mycobacterium bovis</em>, hence zoonotic tuberculosis and other factors. This preliminary study limited to rifampin-resistant isolates, nevertheless paves the way for a genome-based survey of tuberculosis in Central African Republic which is essential for enhancing the management and control of the deadly tuberculosis that is a public health concern in the country.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"152 ","pages":"Article 102627"},"PeriodicalIF":2.8,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143609263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Novel 2-phenylquinolin-4(1H)-one threaded 1,2,3- triazoles were designed, synthesized and evaluated for in vitro activity against Mycobacterium tuberculosis which could be putatively through inhibition of carbonic anhydrase β. Molecules were synthesized in simple Schottan Baumann reaction for amide synthesis. Purified compounds were screened for antitubercular and antibacterial activities. Among them, 1-((1-(2-methoxyphenyl)-1H-1,2,3-triazol-4-yl)methyl)-2-phenylquinolin-4(1H)-one 9j with 2-methoxy at the ortho position of phenyl ring indicated significant antitubercular activity with MIC value of 6.25, 3.12 and 3.12 μg/ml antimicrobial activity against Mycobacterium tuberculosis, gram positive and gram negative strain. The molecular docking and dynamics studies demonstrated that the compound 9j occupied the Zn-binding site of the enzyme with docking energy of -6.2 kcal mol−1. In silico ADME studies indicated that the synthesized compounds have good drug likeliness. The findings explore and present a potential series of antimycobacterial agents in the hope of developing new and advanced therapeutics for tuberculosis.
{"title":"Integrative exploration of 2-phenylquinolin-4(1H)-one tethered 1,2,3-triazole derivatives: A comprehensive in vitro and in silico investigation towards novel anti-tubercular agents","authors":"Raut Mehavi , Walhekar Vinayak , Patil Ashwini , Pavan Kumar Jaini , Mohana Vamsi Nuli , Bhikshapathi DVRN , Ravindra Kulkarni","doi":"10.1016/j.tube.2025.102628","DOIUrl":"10.1016/j.tube.2025.102628","url":null,"abstract":"<div><div>Novel 2-phenylquinolin-4(1<em>H</em>)-one threaded 1,2,3- triazoles were designed, synthesized and evaluated for <em>in vitro</em> activity against <em>Mycobacterium tuberculosis</em> which could be putatively through inhibition of carbonic anhydrase <em>β</em>. Molecules were synthesized in simple Schottan Baumann reaction for amide synthesis. Purified compounds were screened for antitubercular and antibacterial activities. Among them, 1-((1-(2-methoxyphenyl)-1H-1,2,3-triazol-4-yl)methyl)-2-phenylquinolin-4(1<em>H</em>)-one <strong>9j</strong> with 2-methoxy at the ortho position of phenyl ring indicated significant antitubercular activity with MIC value of <strong>6.25, 3.12</strong> and <strong>3.12 μg/ml</strong> antimicrobial activity against <em>Mycobacterium tuberculosis,</em> gram positive and gram negative strain. The molecular docking and dynamics studies demonstrated that the compound <strong>9j</strong> occupied the Zn-binding site of the enzyme with docking energy of <strong>-6.2 kcal mol<sup>−1</sup></strong>. <em>In silico</em> ADME studies indicated that the synthesized compounds have good drug likeliness. The findings explore and present a potential series of antimycobacterial agents in the hope of developing new and advanced therapeutics for tuberculosis.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"152 ","pages":"Article 102628"},"PeriodicalIF":2.8,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143619972","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 : 2025-03-04DOI: 10.1016/j.tube.2025.102629
Sholeh Feizi , Clare M. Cooksley , Nicole Reyne , Bernadette Boog , John Finnie , Gohar Shaghayegh , Karen Hon , Mahnaz Ramezanpour , Alkis J. Psaltis , Peter-John Wormald , Patricia Cmielewski , Alexandra McCarron , Martin Donnelley , David Parsons , Sarah Vreugde
Animal models that can mimic progressive granulomatous pulmonary disease (PD) due to non-tuberculous mycobacteria (NTM) have not been established in rats to date. These models could assist with the study of the pathophysiology of NTM-PD as well as the preclinical development of new therapies. In the present study, an immunocompetent rat model of progressive Mycobacterium abscessus (MABs)- PD was developed using MABs originating from a patient with cystic fibrosis. MABs was embedded in agarose beads and delivered intratracheally to the lungs of Sprague Dawley rats two times at a one-week time interval. The bacterial burden of lysed lungs, spleen and liver was assessed by calculating colony forming units (CFUs) on day 28. Lung CFUs indicated a ∼1.2–2 log10 total CFU increase compared to the initial total bacterial load instilled into the lungs. In all infected rats, multinodular granulomatous inflammatory lesions containing MABs were found in the lung. These findings support the establishment of an immunocompetent MABs PD rat model, characterised by an increase in mycobacterial burden over time and a chronic granulomatous inflammatory response to the MABs infection.
{"title":"An immunocompetent rat model of Mycobacterium abscessus multinodular granulomatous lung infection","authors":"Sholeh Feizi , Clare M. Cooksley , Nicole Reyne , Bernadette Boog , John Finnie , Gohar Shaghayegh , Karen Hon , Mahnaz Ramezanpour , Alkis J. Psaltis , Peter-John Wormald , Patricia Cmielewski , Alexandra McCarron , Martin Donnelley , David Parsons , Sarah Vreugde","doi":"10.1016/j.tube.2025.102629","DOIUrl":"10.1016/j.tube.2025.102629","url":null,"abstract":"<div><div>Animal models that can mimic progressive granulomatous pulmonary disease (PD) due to non-tuberculous mycobacteria (NTM) have not been established in rats to date. These models could assist with the study of the pathophysiology of NTM-PD as well as the preclinical development of new therapies. In the present study, an immunocompetent rat model of progressive <em>Mycobacterium abscessus (MABs)</em>- PD was developed using <em>MABs</em> originating from a patient with cystic fibrosis. <em>MABs</em> was embedded in agarose beads and delivered intratracheally to the lungs of Sprague Dawley rats two times at a one-week time interval. The bacterial burden of lysed lungs, spleen and liver was assessed by calculating colony forming units (CFUs) on day 28. Lung CFUs indicated a ∼1.2–2 log<sub>10</sub> total CFU increase compared to the initial total bacterial load instilled into the lungs. In all infected rats, multinodular granulomatous inflammatory lesions containing <em>MABs</em> were found in the lung. These findings support the establishment of an immunocompetent <em>MABs</em> PD rat model, characterised by an increase in mycobacterial burden over time and a chronic granulomatous inflammatory response to the <em>MABs</em> infection.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"152 ","pages":"Article 102629"},"PeriodicalIF":2.8,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143562533","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号