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Bioinformatics and Biology Insights 2024Tuberculosis (TB) remains a global health challenge with the emergence of drug-resistant Mycobacterium tuberculosis variants, necessitating innovative drug molecules....
Tuberculosis (TB) remains a global health challenge with the emergence of drug-resistant Mycobacterium tuberculosis variants, necessitating innovative drug molecules. One potential target is the cell wall synthesis enzyme decaprenylphosphoryl-β-D-ribose 2'-epimerase (DprE1), crucial for virulence and survival. This study employed virtual screening of 111 Protein Data Bank (PDB) database molecules known for their inhibitory biological activity against DprE1 with known IC50 values. Six compounds, PubChem ID: 390820, 86287492, 155294899, 155522922, 162651615, and 162665075, exhibited promising attributes as drug candidates and validated against clinical trial inhibitors BTZ043, TBA-7371, PBTZ169, and OPC-167832. Concurrently, this research focused on DprE1 mutation effects using molecular dynamic simulations. Among the 10 mutations tested, C387N significantly influenced protein behavior, leading to structural alterations observed through root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), radius of gyration (Rg), and solvent-accessible surface area (SASA) analysis. Ligand 2 (ID: 390820) emerged as a promising candidate through ligand-based pharmacophore analysis, displaying enhanced binding compared with reference inhibitors. Molecular dynamic simulations highlighted ligand 2's interaction with the C387N mutation, reducing fluctuations, augmenting hydrogen bonding, and influencing solvent accessibility. These collective findings emphasize ligand 2's efficacy, particularly against severe mutations, in enhancing protein-ligand complex stability. Integrated computational and pharmacophore methodologies offer valuable insights into drug candidates and their interactions within intricate protein environments. This research lays a strategic foundation for targeted interventions against drug-resistant TB, highlighting ligand 2's potential for advanced drug development strategies.
PubMed: 38812740
DOI: 10.1177/11779322241257039 -
Frontiers in Microbiology 2024Bioinformatic studies on small proteins are under-represented due to difficulties in annotation posed by their small size. However, recent discoveries emphasize the...
Bioinformatic studies on small proteins are under-represented due to difficulties in annotation posed by their small size. However, recent discoveries emphasize the functional significance of small proteins in cellular processes including cell signaling, metabolism, and adaptation to stress. In this study, we utilized a Random Forest classifier trained on sequence features, RNA-Seq, and Ribo-Seq data to uncover small proteins (smORFs) in . Independent predictions for the exponential and starvation conditions resulted in 695 potential smORFs. We examined the functional implications of these smORFs using homology searches, LC-MS/MS, and ChIP-seq data, testing their expression in diverse growth conditions, and identifying protein domains. We provide evidence that some of these smORFs could be part of operons, or exist as upstream ORFs. This expanded data resource for the proteins of would aid in fine-tuning the existing protein and gene regulatory networks, thereby improving system-wide studies. The primary goal of this study was to uncover and characterize smORFs in through bioinformatic analysis, shedding light on their functional roles and genomic organization. Further investigation of these potential smORFs would provide valuable insights into the genome organization and functional diversity of the proteome.
PubMed: 38812687
DOI: 10.3389/fmicb.2024.1335310 -
Central-European Journal of Immunology 2024Until the COVID-19 pandemic, tuberculosis (TB) was the leading cause of death from a single infectious agent, ranking above HIV/AIDS. It is also the key cause of death...
INTRODUCTION
Until the COVID-19 pandemic, tuberculosis (TB) was the leading cause of death from a single infectious agent, ranking above HIV/AIDS. It is also the key cause of death among people infected with HIV. Tuberculosis incidence in Latvia has decreased by 25% during the last 30 years, but the mortality level of TB remains significant. The HLA class II genes are responsible for antigen presentation and regulation of immune responses, which plays an important role in individual susceptibility to infection disease. Whether or not differential HLA polymorphism contributes to TB with HIV infection and TB without HIV infection in Latvian patients is unknown.
MATERIAL AND METHODS
For the detection of HLA class II DQA1, DQB1, and DRB1 alleles a total of 616 subjects were enrolled, including 80 primary active TB (PATB) patients, 168 HIV-1/TB patients, 168 HIV-1 patients and 200 HC individuals.
RESULTS
For immunodeficiency caused by TB, HIV-1 or HIV-1/TB coinfection, alleles DRB1*12:01, 14:01, 16:01, DQA1*01:02, 01:03, 02:01, 06:01, DQB1*03:03, 06:01 are identified as protective, but DRB1*07:01, 11:01, 15:01, DQA1*02:01, 03:01, DQB1*03:01, 05:01 are identified as risk alleles.
CONCLUSIONS
The results of our experimental pilot studies demonstrated that HLA class II genes may contribute to the genetic risk of TB and HIV-1/TB co-infection, possibly by reducing the presentation of protective Mycobacterium tuberculosis antigens to T-helpers. It is necessary to conduct repetitive, multicentre, and large sample studies in order to draw more scientific conclusions and to confirm the relationship between TB, HIV and HIV-1/TB co-infection susceptibility and gene polymorphisms.
PubMed: 38812605
DOI: 10.5114/ceji.2024.138738 -
Communications Biology May 2024
PubMed: 38811662
DOI: 10.1038/s42003-024-06260-z -
Scientific Reports May 2024Tuberculosis (TB), caused by Mycobacterium tuberculosis, has a significant impact on global health worldwide. The development of multi-drug resistant strains that are...
Tuberculosis (TB), caused by Mycobacterium tuberculosis, has a significant impact on global health worldwide. The development of multi-drug resistant strains that are resistant to the first-line drugs isoniazid and rifampicin threatens public health security. Rifampicin and isoniazid resistance are largely underpinned by mutations in rpoB and katG respectively and are associated with fitness costs. Compensatory mutations are considered to alleviate these fitness costs and have been observed in rpoC/rpoA (rifampicin) and oxyR'-ahpC (isoniazid). We developed a framework (CompMut-TB) to detect compensatory mutations from whole genome sequences from a large dataset comprised of 18,396 M. tuberculosis samples. We performed association analysis (Fisher's exact tests) to identify pairs of mutations that are associated with drug-resistance, followed by mediation analysis to identify complementary or full mediators of drug-resistance. The analyses revealed several potential mutations in rpoC (N = 47), rpoA (N = 4), and oxyR'-ahpC (N = 7) that were considered either 'highly likely' or 'likely' to confer compensatory effects on drug-resistance, including mutations that have previously been reported and validated. Overall, we have developed the CompMut-TB framework which can assist with identifying compensatory mutations which is important for more precise genome-based profiling of drug-resistant TB strains and to further understanding of the evolutionary mechanisms that underpin drug-resistance.
Topics: Mycobacterium tuberculosis; Mutation; Genome, Bacterial; Drug Resistance, Multiple, Bacterial; Rifampin; Antitubercular Agents; Isoniazid; Tuberculosis, Multidrug-Resistant; Humans; Bacterial Proteins; Whole Genome Sequencing; Microbial Sensitivity Tests
PubMed: 38811658
DOI: 10.1038/s41598-024-62946-8 -
Dermatology Practical & Conceptual Apr 2024
PubMed: 38810056
DOI: 10.5826/dpc.1402a115 -
PloS One 2024To analyze the results of proficiency testing for anti-tuberculosis drug susceptibility testing (DST) in China. Number of laboratory participating the proficiency...
To analyze the results of proficiency testing for anti-tuberculosis drug susceptibility testing (DST) in China. Number of laboratory participating the proficiency testing performed DST, and the sensitivity, specificity, reproducibility, and accordance rate were calculated from data of 13 rounds proficiency testing results for DST from 2008 to 2021. A total of 30 and 20 strains of Mycobacterium tuberculosis with known susceptibility results were sent to each laboratory in 2008 to 2019, 2020 and 2021, respectively. The number of participating laboratories ranged from 30 in 2009 to 546 in 2021. L-J DST was the predominant method. The specificity presented relatively higher than sensitivity. Improvement of specificity were observed for all drugs through the years, while sensitivity did not show improvement for amikacin and capreomycin. Accordance rate of pyrazinamide and kanamycin and reproducibility of capreomycin and pyrazinamide were not significantly improved through the years. Most of the participating laboratories significantly improved the quality of their DST through the consecutive rounds of proficiency testing except for second-line injectable drugs and pyrazinamide. The results highlight the importance of developing novel and/or improving existing methods for phenotypic DST for certain drugs.
Topics: Mycobacterium tuberculosis; Microbial Sensitivity Tests; China; Antitubercular Agents; Humans; Laboratory Proficiency Testing; Reproducibility of Results; Phenotype; Amikacin; Pyrazinamide
PubMed: 38809914
DOI: 10.1371/journal.pone.0304265 -
Wellcome Open Research 2023The clinical management of leprosy is complicated by leprosy reactions (LR) causing irreversible nerve damage and disabilities. LR often require long-term use of...
Metformin as adjunctive therapy in combination with multidrug treatment for multibacillary leprosy: A protocol for a randomized double-blind, controlled Phase 2 trial in Indonesia (MetLep Trial).
BACKGROUND
The clinical management of leprosy is complicated by leprosy reactions (LR) causing irreversible nerve damage and disabilities. LR often require long-term use of corticosteroids causing serious side effects. Adjunct host-directed therapy (HDT) is a potentially attractive strategy in leprosy to prevent LR and associated immunopathology, modulate immunological memory that protects against recurrence, and thereby reduce nerve damage, disability and corticosteroid-associated morbidities. Metformin, a well-tolerated, safe and cheap anti-hyperglycaemic drug, is repurposed as HDT in auto-immune and infectious diseases, like tuberculosis (TB). Metformin use in people with diabetes is associated with reduced risks of TB-infection, progression to active TB, treatment failure and TB-mortality. Given the similarities both mycobacteria share, we hypothesize that among persons with multibacillary (MB) leprosy, adjunctive metformin may prevent/mitigate LR.
METHODS
We will perform a double-blind controlled proof-of-concept trial in which people with newly diagnosed multibacillary leprosy will be randomized (1:1) to metformin hydrochloride 1000mg extended release once daily versus placebo for 24 weeks in addition to standard-of-care WHO MB multidrug therapy (MDT) during 48 weeks. We aim to enrol 166 participants aged between 18 and 65 years, across five clinical sites in two leprosy endemic areas in Indonesia. Primary outcomes are the proportion of participants experiencing a LR and the frequency of (serious) adverse events. Secondary outcomes are the severity and time to first LR, the cumulative corticosteroid usage, and quality of life. The total study follow-up is 48 weeks.
DISCUSSION
LR signify the most important cause of irreversible nerve damage leading to anatomical deformities and disabilities, imposing a social and financial burden on those affected. Our study aims to evaluate the efficacy, tolerability and safety of adjunct metformin added to MDT in persons with multibacillary leprosy, and explore its effects on clinical and immunological outcomes.
CLINICALTRIALSGOV REGISTRATION
NCT05243654 (17/02/2022).
PubMed: 38808319
DOI: 10.12688/wellcomeopenres.19455.2 -
Cureus Apr 2024is a rare species of non-tuberculosis mycobacteria detected in Japan that causes pulmonary infection and cervical lymphadenitis. Here, we report a case of pulmonary...
is a rare species of non-tuberculosis mycobacteria detected in Japan that causes pulmonary infection and cervical lymphadenitis. Here, we report a case of pulmonary infection caused by , which was difficult to distinguish from (Mtb) infection. A 64-year-old Japanese woman with a history of pulmonarytuberculosis had bloody phlegm, a cough, and discomfort in her chest. Chest computed tomography revealed a cavity, infiltration, and a nodule. A smear test for acid-fast bacilli was positive, a complex transcription reverse-transcription concerted (TRC) test was negative, and an Mtb TRC test was withheld because the internal control was negative. After diluting the specimens, the internal control tested positive, and the sample tested negative. We diagnosed pulmonary infection based on a culture test. In conclusion, attention should be paid to the concentration of bacteria in Mtb TRC test samples, ensuring that the internal control provides expected results.
PubMed: 38807831
DOI: 10.7759/cureus.59207 -
Journal of Biomedical Research May 2024Tumor vaccines are a promising avenue in cancer immunotherapy. Despite the progress in targeting specific immune epitopes, tumor cells lacking them can evade treatment....
Tumor vaccines are a promising avenue in cancer immunotherapy. Despite the progress in targeting specific immune epitopes, tumor cells lacking them can evade treatment. Here, we aimed to construct an efficient tumor vaccine Vac-SM, utilizing shikonin (SKN) to induce immunogenic cell death (ICD) and ( ) as an immune adjuvant to enhance tumor vaccine efficacy. SKN demonstrated a dose-dependent and time-dependent cytotoxic effect on the tumor cell line as seen using the CCK-8 assay and induced ICD in tumor cells by detecting the expression of relevant indicators respectively. Compared to that in the control groups, Vac-SM injection in mouse subcutaneous metastatic tumors significantly inhibited tumor growth and distant tumor growth and improved survival rates. effectively induced bone marrow-derived dendritic cells (DC) maturation and activation and tumor-draining lymph nodes showed increased maturation of DC and a higher proportion of effector memory T-cell subsets with Vac-SM treatment, based on flow cytometry analysis results.Collectively, Vac-SM vaccine effectively induces ICD, improves antigen presentation by DC, activates a specific systemic antitumor T-cell immune response, exhibits favorable safety profile, and holds promise for clinical translation for local tumor immunotherapy.
PubMed: 38807377
DOI: 10.7555/JBR.38.20240049