-
1.
Indole-3-Glycerol Phosphate Synthase From Mycobacterium tuberculosis: A Potential New Drug Target.
Esposito, N, Konas, DW, Goodey, NM
Chembiochem : a European journal of chemical biology. 2022;(2):e202100314
-
-
Free full text
-
Abstract
Tuberculosis (TB), caused by the pathogen Mycobacterium tuberculosis, affects millions of people worldwide. Several TB drugs have lost efficacy due to emerging drug resistance and new anti-TB targets are needed. Recent research suggests that indole-3-glycerol phosphate synthase (IGPS) in M. tuberculosis (MtIGPS) could be such a target. IGPS is a (β/α)8 -barrel enzyme that catalyzes the conversion of 1-(o-carboxyphenylamino)-1-deoxyribulose 5'-phosphate (CdRP) into indole-glycerol-phosphate (IGP) in the bacterial tryptophan biosynthetic pathway. M. tuberculosis over expresses the tryptophan pathway genes during an immune response and inhibition of MtIGPS allows CD4 T-cells to more effectively fight against M. tuberculosis. Here we review the published data on MtIGPS expression, kinetics, mechanism, and inhibition. We also discuss MtIGPS crystal structures and compare them to other IGPS structures to reveal potential structure-function relationships of interest for the purposes of drug design and biocatalyst engineering.
-
2.
Something Old, Something New: Ion Channel Blockers as Potential Anti-Tuberculosis Agents.
Mitini-Nkhoma, SC, Chimbayo, ET, Mzinza, DT, Mhango, DV, Chirambo, AP, Mandalasi, C, Lakudzala, AE, Tembo, DL, Jambo, KC, Mwandumba, HC
Frontiers in immunology. 2021;:665785
Abstract
Tuberculosis (TB) remains a challenging global health concern and claims more than a million lives every year. We lack an effective vaccine and understanding of what constitutes protective immunity against TB to inform rational vaccine design. Moreover, treatment of TB requires prolonged use of multi-drug regimens and is complicated by problems of compliance and drug resistance. While most Mycobacterium tuberculosis (Mtb) bacilli are quickly killed by the drugs, the prolonged course of treatment is required to clear persistent drug-tolerant subpopulations. Mtb's differential sensitivity to drugs is, at least in part, determined by the interaction between the bacilli and different host macrophage populations. Therefore, to design better treatment regimens for TB, we need to understand and modulate the heterogeneity and divergent responses that Mtb bacilli exhibit within macrophages. However, developing drugs de-novo is a long and expensive process. An alternative approach to expedite the development of new TB treatments is to repurpose existing drugs that were developed for other therapeutic purposes if they also possess anti-tuberculosis activity. There is growing interest in the use of immune modulators to supplement current anti-TB drugs by enhancing the host's antimycobacterial responses. Ion channel blocking agents are among the most promising of the host-directed therapeutics. Some ion channel blockers also interfere with the activity of mycobacterial efflux pumps. In this review, we discuss some of the ion channel blockers that have shown promise as potential anti-TB agents.
-
3.
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.
-
4.
Effectiveness of vitamin D supplementation on the outcome of pulmonary tuberculosis treatment in adults: a meta-analysis of randomized controlled trials.
Zhang, J, Chen, C, Yang, J
Chinese medical journal. 2019;(24):2950-2959
-
-
Free full text
-
Abstract
BACKGROUND Tuberculosis (TB) is one of the most debilitating diseases worldwide. Current studies have shown that vitamin D plays a significant role in host immune defense against Mycobacterium tuberculosis, but clinical trials reported inconsistent results. Therefore, we systematically reviewed the literature to investigate whether vitamin D supplementation could improve the effect of anti-TB therapy. METHODS We systematically searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials from their inception to February 8th, 2019 for randomized controlled trials on vitamin D supplementation in patients with pulmonary TB receiving anti-TB therapy. The primary outcomes were time to sputum culture and smear conversion and proportion of participants with negative sputum culture. The secondary outcomes were clinical response to treatment and adverse events. A random-effects model was used to pool studies. Data were analyzed using RevMan 5.3 software. RESULTS Five studies with a total of 1126 participants were included in our meta-analysis. Vitamin D supplementation did not shorten the time to sputum culture and smear conversion (hazard ratio [HR] 1.04, 95% confidence interval [CI] 0.89-1.23, P = 0.60; HR 1.15, 95% CI 0.93-1.41, P = 0.20, respectively) and did not lead to an increase in the proportion of participants with negative sputum culture (relative risk [RR] 1.04, 95% CI 0.97-1.11, P = 0.32). However, it reduced the time to sputum culture conversion in the sub-group of participants with TaqI tt genotype (HR 8.09, 95% CI 1.39-47.09, P = 0.02) and improved the multidrug-resistant (MDR) TB sputum culture conversion rate (RR 2.40, 95% CI 1.11-5.18, P = 0.03). There was no influence on secondary outcomes. CONCLUSIONS Vitamin D supplementation had no beneficial effect on anti-TB treatment, but it reduced the time to sputum culture conversion in participants with tt genotype of the TaqI vitamin D receptor gene polymorphism and improved the MDR TB sputum culture conversion rate.
-
5.
[Not Available].
Mathias, G, Kerwat, K, Wulf, H
Anasthesiologie, Intensivmedizin, Notfallmedizin, Schmerztherapie : AINS. 2016;(3):160-7
Abstract
Tuberculosis is a rare disease in Germany. This is the result of systematic treatment, contact tracing, and supervision of public health institutions, but even more of good nutrition and immunity of the population. Considering migration waves, a higher incidence of non-diagnosed tuberculosis may be expected. Due to the airborne type of infection and constant manipulation of the airway, those working in anesthesia, intensive care and emergency medicine are exposed to an increased risk of infection with tuberculosis. To avoid hospital and community infection, several guidelines of national and international organizations are available.This article gives a summary of the mechanism and probability of infection, diagnosis of infection andpathogen detection; important guidelines are referred to, and everyday situations with risk of infection and their avoidance are described. The message is that self-protection should be possible by information and awareness.
-
6.
Vitamin D supplementation: a comprehensive review on supplementation for tuberculosis prophylaxis.
Turnbull, ER, Drobniewski, F
Expert review of respiratory medicine. 2015;(3):269-75
-
-
Free full text
-
Abstract
Vitamin D plays a large role in the innate immune response against Mycobacterium tuberculosis (MTB) infection, activation and progression. Likewise, vitamin D deficiency is shown by evidence presented here to be a known risk factor for developing both MTB infection and active tuberculosis (TB). This comprehensive review discusses the evidence and remaining questions regarding vitamin D supplementation as a prophylactic measure in those who are at high risk of MTB infection and active TB. Vitamin D supplementation is routinely prescribed for osteoporosis prevention; yet, guidelines are lacking for its prescription for TB prevention, despite the adverse effects being rare. Policymakers are urged here to review the literature and provide urgent guidelines on vitamin D supplementation for TB prophylaxis.
-
7.
Autologous mesenchymal stromal cell infusion as adjunct treatment in patients with multidrug and extensively drug-resistant tuberculosis: an open-label phase 1 safety trial.
Skrahin, A, Ahmed, RK, Ferrara, G, Rane, L, Poiret, T, Isaikina, Y, Skrahina, A, Zumla, A, Maeurer, MJ
The Lancet. Respiratory medicine. 2014;(2):108-22
Abstract
BACKGROUND Novel treatment options are urgently needed for multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis, which are associated with immune dysfunction and poor treatment outcomes. Mesenchymal stromal cells (MSCs) are immunomodulatory and adjunct autologous treatment with bone marrow-derived MSCs might improve clinical outcome by transforming chronic inflammation into productive immune responses. Our aim was to assess the safety of infusion of autologous MSCs as an adjunct treatment in patients with tuberculosis. METHODS 30 patients with microbiologically confirmed MDR or XDR tuberculosis were treated with single-dose autologous bone marrow-derived MSCs (aimed for 1×10(6) cells per kg), within 4 weeks of the start of antituberculosis-drug treatment in a specialist centre in Minsk, Belarus. Inclusion patients were those with pulmonary tuberculosis confirmed by sputum smear microscopy, culture, or both; MDR or XDR tuberculosis confirmed by drug-susceptibility testing to first-line and second-line drugs; age older than 21 years to 65 years or younger; and absence of lesion compatible with a malignant process or ongoing tuberculosis in organs other than the lungs and pleura. In addition to the inclusion criteria, patients were excluded if they were pregnant, coinfected with HIV, or infected with hepatitis B, C, or both. The primary endpoint was safety measured by MSC-infusion related events; any tuberculosis-related event within the 6 month observation period that related to a worsening of the underlying infectious disease, measured by conversion of Mycobacterium tuberculosis culture or microscopic examination; or any adverse event defined clinically or by changes in blood haematology and biochemistry variables, measured monthly for 6 months after MSC infusion per protocol. This study is registered with the German Clinical Trials Registry, number DRKS00000763. FINDINGS The most common (grade 1 or 2) adverse events were high cholesterol levels (14 of 30 patients), nausea (11 of 30 patients), and lymphopenia or diarrhoea (ten of 30 patients). There were no serious adverse events reported. We recorded two grade 3 events that were transitory-ie, increased plasma potassium ion concentrations in one patient and a transitory grade 3 γ-glutamyltransferase elevation in another patient. INTERPRETATION MSCs as an adjunct therapy are safe and can now be explored further for the treatment of patients with MDR or XDR tuberculosis in combination with standard drug regimens. Adjunct treatment with MSCs needs to be evaluated in controlled phase 2 trials to assess effects on immune responses and clinical and microbiological outcomes.
-
8.
Shortening the 'short-course' therapy- insights into host immunity may contribute to new treatment strategies for tuberculosis.
Schön, T, Lerm, M, Stendahl, O
Journal of internal medicine. 2013;(4):368-82
-
-
Free full text
-
Abstract
Achieving global control of tuberculosis (TB) is a great challenge considering the current increase in multidrug resistance and mortality rate. Considerable efforts are therefore being made to develop new effective vaccines, more effective and rapid diagnostic tools as well as new drugs. Shortening the duration of TB treatment with revised regimens and modes of delivery of existing drugs, as well as development of new antimicrobial agents and optimization of the host response with adjuvant immunotherapy could have a profound impact on TB cure rates. Recent data show that chronic worm infection and deficiencies in micronutrients such as vitamin D and arginine are potential areas of intervention to optimize host immunity. Nutritional supplementation to enhance nitric oxide production and vitamin D-mediated effector functions as well as the treatment of worm infection to reduce immunosuppressive effects of regulatory T (Treg) lymphocytes may be more suitable and accessible strategies for highly endemic areas than adjuvant cytokine therapy. In this review, we focus mainly on immune control of human TB, and discuss how current treatment strategies, including immunotherapy and nutritional supplementation, could be optimized to enhance the host response leading to more effective treatment.
-
9.
Immunogenetics of HIV and HIV associated tuberculosis.
Raghavan, S, Alagarasu, K, Selvaraj, P
Tuberculosis (Edinburgh, Scotland). 2012;(1):18-30
Abstract
Tuberculosis (TB) is the frequent major opportunistic infection in HIV-infected patients, and is the leading cause of mortality among HIV-infected patients. Genetic susceptibility to TB in HIV negative subjects is well documented. Since coinfections can influence the way in which immune system respond to different pathogens, genetic susceptibility to TB in HIV patients might also change. Studies from India and other parts of the world have shown that genetic susceptibility to TB is influenced by HIV infection. In the present review, we emphasize the role of genetic factors in determining susceptibility to HIV infection, disease progression and development of TB in HIV-infected patients. Polymorphisms in human leukocyte antigen (HLA), MBL2, CD209, vitamin D receptor, cytokine, chemokine and chemokine receptor genes have been shown to be associated with development of TB in HIV patients. However, the results are inconclusive and larger well-defined studies with precise clinical data are required to validate these associations. Apart from candidate gene approach, genome-wide association studies are also needed to unravel the unknown or to establish the previously reported genetic associations with HIV associated TB. Despite the preliminary status of the reported associations, it is becoming clear that susceptibility to development of TB in HIV patients is influenced by both environmental and genetic components. Understanding the genetic and immunologic factors that influence susceptibility to TB in HIV patients could lead to novel insights for vaccine development as well as diagnostic advances to target treatment to those who are at risk for developing active disease.
-
10.
Polyneuropathy, anti-tuberculosis treatment and the role of pyridoxine in the HIV/AIDS era: a systematic review.
van der Watt, JJ, Harrison, TB, Benatar, M, Heckmann, JM
The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease. 2011;(6):722-8
Abstract
Tuberculosis (TB) is increasing in incidence in certain parts of the world, particularly where there is a co-epidemic of human immunodeficiency virus/acquired immune-deficiency syndrome (HIV/AIDS), and it is associated with a significant degree of morbidity and mortality. One of the most common complications of anti-tuberculosis treatment is the development of a painful isoniazid (INH) associated polyneuropathy (PN), which is preventable with adequate pyridoxine supplementation. As PN is also the most frequent neurological complication associated with HIV infection, subjects who are HIV and TB co-infected may be at increased risk of developing PN. In this review, we explore current knowledge of anti-tuberculosis drug associated PN focusing on INH and its relationship to pyridoxine, as well as the additional impact of antiretroviral treatment and TB-HIV co-infection. It is evident that guidelines established for the prevention and treatment of this problem differ between industrialised and developing countries, and that further research is needed to define the optimum dosing of pyridoxine supplementation in populations where there is a significant burden of TB and HIV.