Current development of 5-nitrofuran-2-yl derivatives as antitubercular agents

Pulmonary tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (MTB) and still remains one of the foremost fatal infectious diseases, infecting nearly a third of the worldwide population. The emergencies of multidrug-resistant and extensively drug-resistant tuberculosis (MDR and XDR-TB) prompt the efforts to deliver potent and novel anti-TB drugs. Research aimed at the development of new anti-TB drugs based on nitrofuran scaffold led to the identification of several candidates that were effective against actively growing as well as latent mycobacteria with unique modes of action. This review focuses on the recent advances in nitrofurans that could provide intriguing potential leads in the area of anti-TB drug discovery.     

Risk of mycobacterial disease among cancer patients: A population-based cohort study in a TB endemic area

ObjectivesTuberculosis (TB) and nontuberculous mycobacteria (NTM) disease have similar symptoms, which makes them difficult to distinguish clinically and leads to the danger of NTM disease being neglected. The aim of this study was to assess the risk of developing mycobacterial disease among cancer patients.MethodsWe conducted a retrospective cohort study using a population-based database. The multivariable Cox proportional hazards model was adjusted to identify independent factors contributing to the development of mycobacterial disease in the cancer cohort.ResultsThe results showed that the increased risk of developing TB and NTM disease was 1.84-fold and 4.43-fold, respectively, in cancer patients compared with the general population. Advanced age (≥65years) and being male were risk factors for developing TB disease. There was a 4.09-fold significantly increased risk of TB disease within six months of a cancer diagnosis. Hematological cancer patients were most likely to develop mycobacterial disease. Younger hematological cancer patients (< 45years) had a higher risk of NTM disease development.ConclusionThere is an increasing risk of mycobacterial disease in cancer patients. We suggest that the possibility of mycobacterial disease in cancer patients should be assessed during the period of cancer therapy, particularly in those who have risk factors.     

Protein tyrosine phosphorylation in Mycobacterium tuberculosis

Abstract Crude cell extracts from three strains of Mycobacterium tuberculosis were analyzed for the presence of proteins possessing phosphorylated tyrosine residues. A protein migrating at approximately 55 kDa was detected using an antiphosphotyrosine monoclonal antibody. In addition, less predominant bands were observed between 50 kDa and 60 kDa. That M. tuberculosis contains specific tyrosine phosphorylated proteins implies that M. tuberculosis has tyrosine kinase activity. Examination of other, non-pathogenic mycobacterium species yielded no major antiphosphotyrosine reactive proteins. This suggests that the antiphosphotyrosine reactive protein is specific to M. tuberculosis strains. These results provide evidence that M. tuberculosis contains an antiphosphotyrosine reactive protein.     

Chemical probes for tagging mycobacterial lipids

Mycobacteria, which cause tuberculosis and related diseases, possess a diverse set of complex envelope lipids that provide remarkable tolerance to antibiotics and are major virulence factors that drive pathogenesis. Recently, metabolic labeling and bio-orthogonal chemistry have been harnessed to develop chemical probes for tagging specific lipids in live mycobacteria, enabling a range of new basic and translational research avenues. A toolbox of probes has been developed for labeling mycolic acids and their derivatives, including trehalose-, arabinogalactan-, and protein-linked mycolates, as well as newer probes for labeling phthiocerol dimycocerosates (PDIMs) and potentially other envelope lipids. These lipid-centric tools have yielded fresh insights into mycobacterial growth and host interactions, provided new avenues for drug target discovery and characterization, and inspired innovative diagnostic and therapeutic strategies.     

Thiazolopyridone ureas as DNA gyrase B inhibitors: Optimization of antitubercular activity and efficacy

Scaffold hopping from the thiazolopyridine ureas led to thiazolopyridone ureas with potent antitubercular activity acting through inhibition of DNA GyrB ATPase activity. Structural diversity was introduced, by extension of substituents from the thiazolopyridone N-4 position, to access hydrophobic interactions in the ribose pocket of the ATP binding region of GyrB. Further optimization of hydrogen bond interactions with arginines in site-2 of GyrB active site pocket led to potent inhibition of the enzyme (IC₅₀ 2 nM) along with potent cellular activity (MIC = 0.1 μM) against Mycobacterium tuberculosis (Mtb). Efficacy was demonstrated in an acute mouse model of tuberculosis on oral administration.     

Design and development of new class of Mycobacterium tuberculosis l-alanine dehydrogenase inhibitors

Mycobacterium tuberculosis l-alanine dehydrogenase (MTB l-AlaDH) is one of the important drug targets for treating latent/persistent tuberculosis. In this study we used crystal structure of the MTB l-AlaDH bound with cofactor NAD⁺ as a structural framework for virtual screening of our in-house database to identified new classes of l-AlaDH inhibitor. We identified azetidine-2,4-dicarboxamide derivative as one of the potent inhibitor with IC₅₀ of 9.22 ± 0.72 μM. Further lead optimization by synthesis leads to compound 1-(isonicotinamido)-N²,N⁴-bis(benzo[d]thiazol-2-yl)azetidine-2,4-dicarboxamide (18) with l-AlaDH IC₅₀ of 3.83 ± 0.12 μM, 2.0 log reduction in nutrient starved dormant MTB model and MIC of 11.81 μM in actively replicative MTB.     

Host biomarkers detected in saliva show promise as markers for the diagnosis of pulmonary tuberculosis disease and monitoring of the response to tuberculosis treatment

BackgroundThere is an urgent need for new tools for the rapid diagnosis of tuberculosis (TB) disease in resource-constrained settings. Tests based on host immunological biomarkers maybe useful, especially if based on easily available samples. We investigated host biomarkers detected in saliva samples from individuals with suspected pulmonary TB disease, as tools for the diagnosis of TB disease and monitoring of the response to treatment.MethodsWe collected saliva samples from 104 individuals that presented with symptoms requiring investigation for TB disease at a primary health care clinic in the outskirts of Cape Town, South Africa, prior to assessment for TB disease. We evaluated the concentrations of 33 host markers in stored saliva samples using a multiplex cytokine platform. Using a combination of clinical, radiological and laboratory results and a pre-established diagnostic algorithm, participants were later classified as having TB disease or other respiratory diseases (ORD). The diagnostic potentials of individual analytes were analysed by the receiver operator characteristics curve approach while the predictive abilities of combinations of analytes for TB disease were analysed by general discriminant analysis, with leave-one-out cross validation.ResultsOf the 104 individuals enrolled, 32 were pulmonary TB cases. There were significant differences in the levels of 10 of the markers investigated between the patients with TB disease and those with ORDs. However, the optimal diagnostic biosignature was a seven-marker combination of salivary CRP, ferritin, serum amyloid P, MCP-1, alpha-2-macroglobulin, fibrinogen and tissue plasminogen activator. This biosignature diagnosed TB disease with a sensitivity of 78.1% (95% CI, 59.6–90.1%) and specificity of 83.3% (95% CI, 72.3–90.7%) after leave-one-out cross validation. When compared to baseline levels, the concentrations of 9 markers including granzyme A, MCP-1, IL-1β, IL-9, IL-10, IL-15, MIP-1β, ferritin and serum amyloid A changed significantly by months 2 or 6 after initiation of TB treatment, thereby indicating that they might be useful in monitoring the response to TB treatment.ConclusionWe have identified candidate biomarkers in saliva, which may be useful in the diagnosis of TB disease and monitoring of the response to TB treatment. These results require further validation in larger studies.     

The impact of a knowledge translation intervention employing educational outreach and a point-of-care reminder tool vs standard lay health worker training on tuberculosis treatment completion rates: study protocol for a cluster randomized controlled trial

BackgroundDespite availability of effective treatment, tuberculosis (TB) remains an important cause of morbidity and mortality globally, with low- and middle-income countries most affected. In many such settings, including Malawi, the high burden of disease and severe shortage of skilled healthcare workers has led to task-shifting of outpatient TB care to lay health workers (LHWs). LHWs improve access to healthcare and some outcomes, including TB completion rates, but lack of training and supervision limit their impact. The goals of this study are to improve TB care provided by LHWs in Malawi by refining, implementing, and evaluating a knowledge translation strategy designed to address a recognized gap in LHWs’ TB and job-specific knowledge and, through this, to improve patient outcomes.Methods/designWe are employing a mixed-methods design that includes a pragmatic cluster randomized controlled trial and a process evaluation using qualitative methods. Trial participants will include all health centers providing TB care in four districts in the South East Zone of Malawi. The intervention employs educational outreach, a point-of-care reminder tool, and a peer support network. The primary outcome is proportion of treatment successes, defined as the total of TB patients cured or completing treatment, with outcomes taken from Ministry of Health treatment records. With an alpha of 0.05, power of 0.80, a baseline treatment success of 0.80, intraclass correlation coefficient of 0.1 based on our pilot study, and an estimated 100 clusters (health centers providing TB care), a minimum of 6 patients per cluster is required to detect a clinically significant 0.10 increase in the proportion of treatment successes. Our process evaluation will include interviews with LHWs and patients, and a document analysis of LHW training logs, quarterly peer trainer meetings, and mentorship meeting notes. An estimated 10–15 LHWs and 10–15 patients will be required to reach saturation in each of 2 planned interview periods, for a total of 40–60 interview participants.DiscussionThis study will directly inform the efforts of knowledge users within TB care and, through extension of the approach, other areas of care provided by LHWs in Malawi and other low- and middle-income countries.

Trial registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT02533089","term_id":"NCT02533089"}}NCT02533089. Registered 20 August 2015. Protocol Date/Version 29 May 2016/Version 2.

Electronic supplementary material

The online version of this article (doi:10.1186/s13063-016-1563-2) contains supplementary material, which is available to authorized users.     

特殊人群肺结核患者抗结核治疗期间不良反应分析

目的 探讨老年人、儿童、营养不良及合并其他慢性疾病等特殊人群肺结核患者在抗结核治疗期间药物不良反应情况,为其临床调整用药提供相关依据,以降低特殊人群肺结核治疗中不良反应发生.方法 由结核科专业医师查阅2007年1月至2012年12月病例资料,包括住院病历、病程记录、服药记录、实验室检查等,回顾性分析特殊人群肺结核患者药物所致不良反应的发生情况.结果 特殊人群肺结核患者抗结核治疗药物不良反应发生率达43.1％,显著高于非特殊人群的29.7％(P＜0.05),特殊人群组不良反应出现的时间平均为24.3d,显著早于非特殊人群组的33.7d(P＜0.05).特殊人群97.7％的不良反应发生在服药后2个月内,而非特殊人群服药2个月内发生不良反应率为83.5％(P＜0.05).结论 特殊人群肺结核患者抗结核治疗期间药物不良反应发生时间较早、发生率较高,特殊人群要加强不良反应监测.