Tetrahydropyrazolo[1,5-a]Pyrimidine-3-Carboxamide and N-Benzyl-6′,7′-Dihydrospiro[Piperidine-4,4′-Thieno[3,2-c]Pyran] analogues with bactericidal efficacy against Mycobacterium tuberculosis targeting MmpL3

Mycobacterium tuberculosis is a major human pathogen and the causative agent for the pulmonary disease, tuberculosis (TB). Current treatment programs to combat TB are under threat due to the emergence of multi-drug and extensively-drug resistant TB. As part of our efforts towards the discovery of new anti-tubercular leads, a number of potent tetrahydropyrazolo[1,5-a]pyrimidine-3-ca​rboxamide(THPP) and N-benzyl-6′,7′-dihydrospiro[piperidine-4,​4′-thieno[3,2-c]pyran](Spiro) analogues were recently identified against Mycobacterium tuberculosis and Mycobacterium bovis BCG through a high-throughput whole-cell screening campaign. Herein, we describe the attractive in vitro and in vivo anti-tubercular profiles of both lead series. The generation of M. tuberculosis spontaneous mutants and subsequent whole genome sequencing of several resistant mutants identified single mutations in the essential mmpL3 gene. This ‘genetic phenotype’ was further confirmed by a ‘chemical phenotype’, whereby M. bovis BCG treated with both the THPP and Spiro series resulted in the accumulation of trehalose monomycolate. In vivo efficacy evaluation of two optimized THPP and Spiro leads showed how the compounds were able to reduce >2 logs bacterial cfu counts in the lungs of infected mice

Tubercular dactylitis in a 65 year old female: a rare case report

Tubercular dactylitis is defined as tubercular infection of the metacarpals, metatarsals and phalanges. It is a rare form of extra pulmonary tuberculosis. Bones of the hand are more commonly affected than the bones of the feet. Tubercular dactylitis is common in children and children below 6 year of age accounts for 85% of cases. The diagnosis is usually by a combination of clinical suspicion coupled with radiological investigation and confirmation by biopsy. We hereby present a case report of tubercular dactylitis in a 65 year old female which was treated by antitubercular therapy

Diagnostic accuracy of multidetector computed tomography scan in mediastinal masses assuming histopathological findings as gold standard

Purpose: Aim of the study was to: 1) present MDCT characteristics of different mediastinal mass lesions, 2) estimate proportion of benign and malignant mediastinal mass lesions based on MDCT findings, and 3) find out the diagnostic accuracy with sensitivity, specificity, positive predictive value, and negative predictive value of MDCT in mediastinal mass lesions assuming histopathology as gold standard. Material and methods: This study was an analysis of 60 patients who underwent MDCT scan for characterisation of mediastinal mass lesion, and subsequently imaging findings were verified with pathological diagnosis. Results: Out of 60 patients 65% were malignant and 35% were benign. Metastatic carcinoma was the leading diagnosis. Sensitivity of MDCT in this study came out to be 94%, specificity is 90%, with a positive predictive value of 94% and negative predictive value of 90% with diagnostic accuracy of 93%. Conclusions: Mediastinal mass lesion can be accurately diagnosed with MDCT which is a non-invasive and easily available modality requiring clinical data for accurate diagnosis and management. Co-relation of MDCT findings with other imaging findings is complex and requires adequate clinical data for optimum diagnostic confidence

Structure based de novo design of IspD inhibitors as anti-tubercular agents

Tuberculosis is one of the leading contagious diseases, caused by Mycobacterium tuberculosis. Despite improvements in anti-tubercular agents, it remains one of the most prevalent infectious diseases worldwide, responsible for a total of 1.6 million deaths annually. The emergence of multidrug resistant strains highlighted the need of discovering novel drug targets for the development of anti-tubercular agents. 2-C-methyl-D-erythritol-4-phosphate cytidyltransferase (IspD) is an enzyme involved in MEP pathway for isoprenoid biosynthesis, which is considered an attractive target for the discovery of novel antibiotics for its essentiality in bacteria and absence in mammals. In the present study, we have employed structure based drug design approach to develop novel and potent inhibitors for IspD receptor. To explore binding affinity and hydrogen bond interaction between the ligand and active site of IspD receptor, docking studies were performed. ADMET and synthetic accessibility filters were used to screen designed molecules. Finally, ten compounds were selected and subsequently submitted for the synthesis and in vitro studies as IspD inhibitors

Intracranial tuberculous mass lesions treated with thalidomide in an immunocompetent child from a low tuberculosis endemic country: A case report

Rationale: Tuberculous meningitis is a highly morbid, often fatal disease. Patient concern: We describe a case of an Italian child. Diagnoses: we diagnosed early a Tuberculous meningitis complicated by the occurrence of hydrocephalus, stroke, and paradoxical reaction with brain pseudo-abscesses. Interventions: The child started readily a specific therapy associated with steroids and thalidomide was introduced few month later. Outcomes: the patient had a favorable outcome without neurologic sequelae. Lessons: Despite the prompt specific anti-tubercular and adjuvant corticosteroid therapies, only the addition of thalidomide to the treatment allow to a favorable clinical outcome

Leptomeningitis in a person with radiologically isolated syndrome and latent tuberculosis. A case report with implications for clinical research

A 39-year-old man, followed with serial MRI of CNS for a radiologically isolate syndrome (RIS, a recently described condition considered a subclinical form of MS), was hospitalized for the occurrence of a leptomeningitis. Routine blood tests and contrast enhanced total body CT scan were unremarkable. Cerebrospinal fluid (CSF) examination showed increase of cells (22 mononuclear cells/mm3), albumin (294 mg/L), immunoglobilins G (161 mg/L) and Link Index (1.9), with 17 oligoclonal bands. Microbiological examinations of CSF (including those for Koch’s Bacillus) were negative. The Mantoux reaction and the QuantiFERON test were positive, featuring a latent tuberculosis (TB). The patient started prophylaxis with rifampicin and isoniazid for four months, until a new MRI showed the disappearance of the leptomeningeal enhancement, and the stability of white matter brain and spinal cord lesions. Two other MRI scans showed a new brain Gd-enhancing lesion nine month after anti-tubercular therapy and, after additional six months, new cerebral and spinal cord areas. This case provides the following suggestions about the effects of TB infection and related therapies on the underlying autoimmune status: the infection, while actively present, did not exacerbate the RIS condition; the worsening nine months after the prophylaxis discontinuation might have been the ‘natural’ evolution of RIS condition. Alternative speculative hypotheses include a remote effect of the infection, of isoniazid (that was reported in some cases to trigger MS), or the result of the clearance of the infection itself. Irrespective of the existence of any interaction between RIS and TB infection, It seems important to collect cases with MS-related diseases and concomitant infections, that may provide clues about disease pathogenesis and treatment

Adenosine deaminase and interferon-gamma in diagnosis of tubercular pleural effusion

Background: Pleural effusion is a common extrapulmonary manifestation of tuberculosis (TB). The conventional culture suffers from lack of sensitivity. Many pleural fluid markers have been evaluated to diagnose tubercular pleural fluid but none has proved to be an ideal. We have studied Adenosine deaminase (ADA), Interferon gamma (IFN) and their combination for diagnosis of tubercular pleural effusion.Methods: All consecutive patients with pleural effusion were subjected to thoracentesis and segregated into transudative and exudative using Light`s criteria. Patients with exudative pleural effusion were enrolled and divided into two groups. Group-I comprised of patients with tubercular etiology, Group-II- non-tubercular etiology. 45 patients were selected for each group. ADA and IFN in pleural fluid of these patients were measured. The sensitivity, specificity and predictive values were calculated.Results: The  sensitivity, specificity, positive predictive value, negative predictive value of ADA and IFN were 88.89%, 99.85%, 86.96%, 99.87%; 97.78%, 97.78%, 97.78%, 97.78% respectively. Combination of ADA and IFN didn’t improve the sensitivity or specificity compared to IFN alone.Conclusions: Pleural fluid ADA, IFN were found to be useful in differentiating tubercular from non-tubercular patients. Combination of ADA and IFN doesn’t give additional benefit over IFN alone

A study of low level nitrogen laser therapy in the treatment of non-responding tubercular lymphadenopathy and sinuses

Forty-four cases of tubercular lymphadenopathy and sinuses, who were taking anti-tubercular treatment for more than 6 months and not responding to it, were randomly selected in this study. Overall cure rate in cases of lymphadenopathy was 93.99% , sinus 77.77% and cold abscess 100%. Mean age of the patients was 30.13 (Male: female1:4.5). Most common site of lymphadenopathy was cervical , smear was positive in 19(43.18%) cases and culture in 25(56.81%) cases. Low Level Nitrogen Laser Therapy may be used as an adjuvant to anti-tubercular drugs in cases of chronic non-responding tubercular lymphadenopathy and sinuses

Neoteric advancement in TB drugs and an overview on the anti-tubercular role of peptides through computational approaches

Peptides of varied origins such as human immune cells and non-immune cells, bacteria, fungi, and venoms have been widely investigated as anti-tubercular agents for the replacement of existing anti-tubercular drugs in future. In the present review, we spotlighted not only on the mechanisms of action and mode of administration of currently available anti-tubercular drugs but also the recent comprehensive report of World Health Organization (WHO) on TB epidemic, diagnosis, prevention, and treatment. The major excerpt of the study also inspects the direct contribution of different computational tools during drug designing strategies against M. tuberculosis in order to grasp the interplay between anti-tubercular peptides and targeted bacterial protein. The potentiality of some of these anti-tubercular peptides as therapeutic agents unlocks a new portal for achieving the goal of end TB strategy.Tuberculosis (TB) is a devastating threat to human health whose treatment without the emergence of drug resistant Mycobacterium tuberculosis (M. tuberculosis) is the million-dollar question at present. The pathogenesis of M. tuberculosis has been extensively studied which represents unique defence strategies by infecting macrophages. Several anti-tubercular drugs with varied mode of action and administration from diversified sources have been used for the treatment of TB that later contributed to the emergence of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB). However, few of potent anti-tubercular drugs are scheduled for clinical trials status in 2017–2018