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The risk of tuberculosis in children after close exposure: a systematic review and individual-participant meta-analysis.
Martinez, L, Cords, O, Horsburgh, CR, Andrews, JR, ,
Lancet (London, England). 2020;(10228):973-984
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Abstract
BACKGROUND Tens of millions of children are exposed to Mycobacterium tuberculosis globally every year; however, there are no contemporary estimates of the risk of developing tuberculosis in exposed children. The effectiveness of contact investigations and preventive therapy remains poorly understood. METHODS In this systematic review and meta-analysis, we investigated the development of tuberculosis in children closely exposed to a tuberculosis case and followed for incident disease. We restricted our search to cohort studies published between Jan 1, 1998, and April 6, 2018, in MEDLINE, Web of Science, BIOSIS, and Embase electronic databases. Individual-participant data and a pre-specified list of variables were requested from authors of all eligible studies. These included characteristics of the exposed child, the index case, and environmental characteristics. To be eligible for inclusion in the final analysis, a dataset needed to include: (1) individuals below 19 years of age; (2) follow-up for tuberculosis for a minimum of 6 months; (3) individuals with household or close exposure to an individual with tuberculosis; (4) information on the age and sex of the child; and (5) start and end follow-up dates. Studies assessing incident tuberculosis but without dates or time of follow-up were excluded. Our analysis had two primary aims: (1) estimating the risk of developing tuberculosis by time-period of follow-up, demographics (age, region), and clinical attributes (HIV, tuberculosis infection status, previous tuberculosis); and (2) estimating the effectiveness of preventive therapy and BCG vaccination on the risk of developing tuberculosis. We estimated the odds of prevalent tuberculosis with mixed-effects logistic models and estimated adjusted hazard ratios (HRs) for incident tuberculosis with mixed-effects Poisson regression models. The effectiveness of preventive therapy against incident tuberculosis was estimated through propensity score matching. The study protocol is registered with PROSPERO (CRD42018087022). FINDINGS In total, study groups from 46 cohort studies in 34 countries-29 (63%) prospective studies and 17 (37%) retrospective-agreed to share their data and were included in the final analysis. 137 647 tuberculosis-exposed children were evaluated at baseline and 130 512 children were followed for 429 538 person-years, during which 1299 prevalent and 999 incident tuberculosis cases were diagnosed. Children not receiving preventive therapy with a positive result for tuberculosis infection had significantly higher 2-year cumulative tuberculosis incidence than children with a negative result for tuberculosis infection, and this incidence was greatest among children below 5 years of age (19·0% [95% CI 8·4-37·4]). The effectiveness of preventive therapy was 63% (adjusted HR 0·37 [95% CI 0·30-0·47]) among all exposed children, and 91% (adjusted HR 0·09 [0·05-0·15]) among those with a positive result for tuberculosis infection. Among all children <5 years of age who developed tuberculosis, 83% were diagnosed within 90 days of the baseline visit. INTERPRETATION The risk of developing tuberculosis among exposed infants and young children is very high. Most cases occurred within weeks of contact investigation initiation and might not be preventable through prophylaxis. This suggests that alternative strategies for prevention are needed, such as earlier initiation of preventive therapy through rapid diagnosis of adult cases or community-wide screening approaches. FUNDING National Institutes of Health.
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Cross-validation of existing signatures and derivation of a novel 29-gene transcriptomic signature predictive of progression to TB in a Brazilian cohort of household contacts of pulmonary TB.
Leong, S, Zhao, Y, Ribeiro-Rodrigues, R, Jones-López, EC, Acuña-Villaorduña, C, Rodrigues, PM, Palaci, M, Alland, D, Dietze, R, Ellner, JJ, et al
Tuberculosis (Edinburgh, Scotland). 2020;:101898
Abstract
The goal of this study was to identify individuals at risk of progression and reactivation among household contacts (HHC) of pulmonary TB cases in Vitoria, Brazil. We first evaluated the predictive performance of six published signatures on the transcriptional dataset obtained from peripheral blood mononuclear cell samples from HHC that either progressed to TB disease or not (non-progressors) during a five-year follow-up. The area under the curve (AUC) values for the six signatures ranged from 0.670 to 0.461, and the PPVs did not reach the WHO published target product profiles (TPPs). We therefore used as training cohort the earliest time-point samples from the African cohort of adolescents (GSE79362) and applied an ensemble feature selection pipeline to derive a novel 29-gene signature (PREDICT29). PREDICT29 was tested on 16 progressors and 21 non-progressors. PREDICT29 performed better in segregating progressors from non-progressors in the Brazil cohort with the area under the curve (AUC) value of 0.911 and PPV of 20%. This proof of concept study demonstrates that PREDICT29 can predict risk of progression/reactivation to clinical TB disease in recently exposed individuals at least 5 years prior to disease development. Upon validation in larger and geographically diverse cohorts, PREDICT29 can be used to risk-stratify recently infected for targeted therapy.
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Synthesis of New 3-Arylaminophthalides and 3-Indolyl-phthalides using Ammonium Chloride, Evaluation of their Anti-Mycobacterial Potential and Docking Study.
Patil, A, Duggal, H, Bagul, KT, Kamble, S, Lokhande, P, Gacche, R, Meshram, R
Combinatorial chemistry & high throughput screening. 2020;(8):723-739
Abstract
OBJECTIVE The study aims at the derivatization of "Phthalides" and synthesizes 3- arylaminophthalides & 3-indolyl-phthalides compounds, and evaluates their anti-tubercular and antioxidant activities. The study has also intended to employ the in silico methods for the identification of possible drug targets in Mycobacterium and evaluate the binding affinities of synthesized compounds. METHODS This report briefly explains the synthesis of phthalide derivatives using ammonium chloride. The synthesized compounds were characterized using spectral analysis. Resazurin Microtiter Assay (REMA) plate method was used to demonstrate the anti-mycobacterial activity of the synthesized compounds. An in-silico pharmacophore probing approach was used for target identification in Mycobacterium. The structural level interaction between the identified putative drug target and synthesized phthalides was studied using Lamarckian genetic algorithm-based software. RESULTS AND DISCUSSION In the present study, we report an effective, environmentally benign scheme for the synthesis of phthalide derivatives. Compounds 5c and 5d from the current series appear to possess good anti-mycobacterial activity. dCTP: deaminasedUTPase was identified as a putative drug target in Mycobacterium. The docking results clearly showed the interactive involvement of conserved residues of dCTP with the synthesized phthalide compounds. CONCLUSION On the eve of evolving anti-TB drug resistance, the data on anti-tubercular and allied activities of the compounds in the present study demonstrates the enormous significance of these newly synthesized derivatives as possible candidate leads in the development of novel anti-tubercular agents. The docking results from the current report provide a structural rationale for the promising anti-tubercular activity demonstrated by 3-arylaminophthalides and 3-indolyl-phthalides compounds.
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A genetic programming-based approach to identify potential inhibitors of serine protease of Mycobacterium tuberculosis.
Kumari, M, Tiwari, N, Subbarao, N
Future medicinal chemistry. 2020;(2):147-159
Abstract
Aim: We applied genetic programming approaches to understand the impact of descriptors on inhibitory effects of serine protease inhibitors of Mycobacterium tuberculosis (Mtb) and the discovery of new inhibitors as drug candidates. Materials & methods: The experimental dataset of serine protease inhibitors of Mtb descriptors was optimized by genetic algorithm (GA) along with the correlation-based feature selection (CFS) in order to develop predictive models using machine-learning algorithms. The best model was deployed on a library of 918 phytochemical compounds to screen potential serine protease inhibitors of Mtb. Quality and performance of the predictive models were evaluated using various standard statistical parameters. Result: The best random forest model with CFS-GA screened 126 anti-tubercular agents out of 918 phytochemical compounds. Also, genetic programing symbolic classification method is optimized descriptors and developed an equation for mathematical models. Conclusion: The use of CFS-GA with random forest-enhanced classification accuracy and predicted new serine protease inhibitors of Mtb, which can be used for better drug development against tuberculosis.
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Infant TB Infection Prevention Study (iTIPS): a randomised trial protocol evaluating isoniazid to prevent M. tuberculosis infection in HIV-exposed uninfected children.
LaCourse, SM, Richardson, BA, Kinuthia, J, Warr, AJ, Maleche-Obimbo, E, Matemo, D, Cranmer, LM, Escudero, JN, Hawn, TR, John-Stewart, GC
BMJ open. 2020;(1):e034308
Abstract
INTRODUCTION HIV-exposed uninfected (HEU) infants in tuberculosis (TB) endemic settings are at high risk of Mycobacterium tuberculosis (Mtb) infection and TB disease, even in the absence of known Mtb exposure. Because infancy is a time of rapid progression from primary infection to active TB disease, it is important to define when and how TB preventive interventions exert their effect in order to develop effective prevention strategies in this high-risk population. METHODS AND ANALYSIS We designed a non-blinded randomised controlled trial to determine efficacy of isoniazid (INH) to prevent primary Mtb infection among HEU children. Target sample size is 300 (150 infants in each arm). Children are enrolled at 6 weeks of age from maternal and child health clinics in Kenya and are randomised to receive 12 months of daily INH ~10 mg/kg plus pyridoxine or no INH. The primary endpoint is Mtb infection, assessed by interferon-gamma release assay QuantiFERON-TB Gold Plus (QFT-Plus) or tuberculin skin test after 12 months post-enrolment. Secondary outcomes include severe adverse events, expanded Mtb infection definition using additional QFT-Plus supernatant markers and determining correlates of Mtb infection. Exploratory analyses include a combined outcome of TB infection, disease and mortality, and sensitivity analyses excluding infants with baseline TB-specific responses on flow cytometry. ETHICS AND DISSEMINATION An external and independent Data and Safety Monitoring Board monitors adverse events. Results will be disseminated through peer-reviewed journals, presentations at local and international conferences to national and global policy-makers, the local community and participants. TRIAL REGISTRATION NUMBER NCT02613169; Pre-results.
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Reductive Stress: New Insights in Physiology and Drug Tolerance of Mycobacterium.
Mavi, PS, Singh, S, Kumar, A
Antioxidants & redox signaling. 2020;(18):1348-1366
Abstract
Significance:Mycobacterium tuberculosis (Mtb) encounters reductive stress during its infection cycle. Notably, host-generated protective responses, such as acidic pH inside phagosomes and lysosomes, exposure to glutathione in alveolar hypophase (i.e., a thin liquid lining consisting of surfactant and proteins in the alveolus), and hypoxic environments inside granulomas are associated with the accumulation of reduced cofactors, such as nicotinamide adenine dinucleotide (reduced form), nicotinamide adenine dinucleotide phosphate, flavin adenine dinucleotide (reduced form), and nonprotein thiols (e.g., mycothiol), leading to reductive stress in Mtb cells. Dissipation of this reductive stress is important for survival of the bacterium. If reductive stress is not dissipated, it leads to generation of reactive oxygen species, which may be fatal for the cells. Recent Advances: This review focuses on mechanisms utilized by mycobacteria to sense and respond to reductive stress. Importantly, exposure of Mtb cells to reductive stress leads to growth inhibition, altered metabolism, modulation of virulence, and drug tolerance. Mtb is equipped with thiol buffering systems of mycothiol and ergothioneine to protect itself from various redox stresses. These systems are complemented by thioredoxin and thioredoxin reductase (TR) systems for maintaining cellular redox homeostasis. A diverse array of sensors is used by Mycobacterium for monitoring its intracellular redox status. Upon sensing reductive stress, Mtb uses a flexible and robust metabolic system for its dissipation. Branched electron transport chain allows Mycobacterium to function with different terminal electron acceptors and modulate proton motive force to fulfill energy requirements under diverse scenarios. Interestingly, Mtb utilizes variations in the tricarboxylic cycle and a number of dehydrogenases to dissipate reductive stress. Upon prolonged exposure to reductive stress, Mtb utilizes biosynthesis of storage and virulence lipids as a dissipative mechanism. Critical Issues: The mechanisms utilized by Mycobacterium for sensing and tackling reductive stress are not well characterized. Future Directions: The precise role of thiol buffering and TR systems in neutralizing reductive stress is not well defined. Genetic systems that respond to metabolic reductive stress and thiol reductive stress need to be mapped. Genetic screens could aid in identification of such systems. Given that management of reductive stress is critical for both actively replicating and persister mycobacteria, an improved understanding of the mechanisms used by mycobacteria for dissipation of reductive stress may lead to identification of vulnerable choke points that could be targeted for killing Mtb in vivo.
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Genome-wide identification of the context-dependent sRNA expression in Mycobacterium tuberculosis.
Ami, VKG, Balasubramanian, R, Hegde, SR
BMC genomics. 2020;(1):167
Abstract
BACKGROUND Tuberculosis remains one of the leading causes of morbidity and mortality worldwide. Therefore, understanding the pathophysiology of Mycobacterium tuberculosis is imperative for developing new drugs. Post-transcriptional regulation plays a significant role in microbial adaptation to different growth conditions. While the proteins associated with gene expression regulation have been extensively studied in the pathogenic strain M. tuberculosis H37Rv, post-transcriptional regulation involving small RNAs (sRNAs) remains poorly understood. RESULTS We developed a novel moving-window based approach to detect sRNA expression using RNA-Seq data. Overlaying ChIP-seq data of RNAP (RNA Polymerase) and NusA suggest that these putative sRNA coding regions are significantly bound by the transcription machinery. Besides capturing many experimentally validated sRNAs, we observe the context-dependent expression of novel sRNAs in the intergenic regions of M. tuberculosis genome. For example, ncRv11806 shows expression only in the stationary phase, suggesting its role in mycobacterial latency which is a key attribute to long term pathogenicity. Also, ncRv11875C showed expression in the iron-limited condition, which is prevalent inside the macrophages of the host cells. CONCLUSION The systems level analysis of sRNA highlights the condition-specific expression of sRNAs which might enable the pathogen survival by rewiring regulatory circuits.
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Isoniazid-phytochemical conjugation: A new approach for potent and less toxic anti-TB drug development.
Swain, SS, Paidesetty, SK, Padhy, RN, Hussain, T
Chemical biology & drug design. 2020;(2):714-730
Abstract
Mycobacterium tuberculosis (Mtb) causes one of the most grievous pandemic infectious diseases, tuberculosis (TB), with long-term morbidity and high mortality. The emergence of drug-resistant Mtb strains, and the co-infection with human immunodeficiency virus, challenges the current WHO-TB stewardship programs. The first-line anti-TB drugs, isoniazid (INH) and rifampicin (RIF), have become extensively obsolete in TB control from chromosomal mutations during the last decades. However, based on clinical trial statistics, the production of well-tolerated anti-TB drug(s) is miserably low. Alternately, semi-synthesis or structural modifications of first-line obsolete antitubercular drugs remain as the versatile approach for getting some potential medicines. The use of any suitable phytochemicals with INH in a hybrid formulation could be an ideal approach for the development of potent anti-TB drug(s). The primary objective of this review was to highlight and analyze available INH-phytochemical hybrid research works. The utilization of phytochemicals through chemical conjugation is a new trend toward the development of safer/non-toxic anti-TB drugs.
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Unique structural and mechanistic properties of mycobacterial F-ATP synthases: Implications for drug design.
Kamariah, N, Ragunathan, P, Shin, J, Saw, WG, Wong, CF, Dick, T, Grüber, G
Progress in biophysics and molecular biology. 2020;:64-73
Abstract
The causative agent of Tuberculosis (TB) Mycobacterium tuberculosis (Mtb) encounters unfavourable environmental conditions in the lungs, including nutrient limitation, low oxygen tensions and/or low/high pH values. These harsh conditions in the host triggers Mtb to enter a dormant state in which the pathogen does not replicate and uses host-derived fatty acids instead of carbohydrates as an energy source. Independent to the energy source, the bacterium's energy currency ATP is generated by oxidative phosphorylation, in which the F1FO-ATP synthase uses the proton motive force generated by the electron transport chain. This catalyst is essential in Mtb and inhibition by the diarylquinoline class of drugs like Bedaquilline, TBAJ-587, TBAJ-876 or squaramides demonstrated that this engine is an attractive target in TB drug discovery. A special feature of the mycobacterial F-ATP synthase is its inability to establish a significant proton gradient during ATP hydrolysis, and its latent ATPase activity, to prevent energy waste and to control the membrane potential. Recently, unique epitopes of mycobacterial F1FO-ATP synthase subunits absent in their prokaryotic or mitochondrial counterparts have been identified to contribute to the regulation of the low ATPase activity. Most recent structural insights into individual subunits, the F1 domain or the entire mycobacterial enzyme added to the understanding of mechanisms, regulation and differences of the mycobacterial F1FO-ATP synthase compared to other bacterial and eukaryotic engines. These novel insights provide the basis for the design of new compounds targeting this engine and even novel regimens for multidrug resistant TB.
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The effect of micro-nutrients on malnutrition, immunity and therapeutic effect in patients with pulmonary tuberculosis: A systematic review and meta-analysis of randomised controlled trials.
Haiqing Cai, , Chen, L, Yin, C, Liao, Y, Meng, X, Lu, C, Tang, S, Li, X, Wang, X
Tuberculosis (Edinburgh, Scotland). 2020;:101994
Abstract
OBJECTIVE Micro-nutrients are closely related to pulmonary tuberculosis (PTB). Most patients with PTB suffer from micro-nutrients deficiency. We aimed to evaluate the efficacy of micro-nutrients support on clinical therapy and chronic inflammation in patients with PTB. METHODS We searched Pubmed, Springer link, Web of Science, Cochrane, Wan Fang and CNKI databases for randomised controlled trials (RCTs). The patients with anti-TB treatments were divided into two groups, the control group with nutritional advice or placebo, and the experimental group with micro-nutrients support for more than 2 weeks. Two reviewers conducted data extraction and quality assessment of the studies independently, and ReviewManager 5.2 software was used to input and analyse the data. The dichotomous variable was expressed in the risk ratios (RRS) and 95% CI, the continuous data were expressed in the mean difference (MD) and 95% CI, and the heterogeneity of subgroup was evaluated by I (Kerantzas and Jacobs, Jr., 2017) [2] test. RESULTS A total of 13 trials (2847 participants) were included. First, micro-nutrients improved sputum smears or culture negative conversion rates (OR 0.16 0.03-0.77, 2.29; MD -2.36, -4.72~-0.01, z = 1.97). Meanwhile, micro-nutrients support increased lymphocytes and decreased leukocytes, neutrophils, CRP and ESR (MD 0.20, 0.06-0.35, z = 2.78; MD -0.42, -0.65~-0.18, z = 3.48; MD -0.66, -1.12~-0.20, z = 2.82). However it had not impact on body weight, MUAC, haemoglobin, albumin or monocytes (p > 0.05). CONCLUSION Micro-nutrients support can reduce chronic inflammation and improve sputum smears or culture conversions to contribute to anti-TB treatment.