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Kubler A.,Imperial College London | Kubler A.,Johns Hopkins University | Luna B.,Johns Hopkins University | Larsson C.,Umea University | And 26 more authors.
Journal of Pathology | Year: 2015

Active tuberculosis (TB) often presents with advanced pulmonary disease, including irreversible lung damage and cavities. Cavitary pathology contributes to antibiotic failure, transmission, morbidity and mortality. Matrix metalloproteinases (MMPs), in particular MMP-1, are implicated in TB pathogenesis. We explored the mechanisms relating MMP/TIMP imbalance to cavity formation in a modified rabbit model of cavitary TB. Our model resulted in consistent progression of consolidation to human-like cavities (100% by day 28), with resultant bacillary burdens (>107 CFU/g) far greater than those found in matched granulomatous tissue (105 CFU/g). Using a novel, breath-hold computed tomography (CT) scanning and image analysis protocol, we showed that cavities developed rapidly from areas of densely consolidated tissue. Radiological change correlated with a decrease in functional lung tissue, as estimated by changes in lung density during controlled pulmonary expansion (R2 = 0.6356, p < 0.0001). We demonstrated that the expression of interstitial collagenase (MMP-1) was specifically greater in cavitary compared to granulomatous lesions (p < 0.01), and that TIMP-3 significantly decreased at the cavity surface. Our findings demonstrated that an MMP-1/TIMP imbalance is associated with the progression of consolidated regions to cavities containing very high bacterial burdens. Our model provided mechanistic insight, correlating with human disease at the pathological, microbiological and molecular levels. It also provided a strategy to investigate therapeutics in the context of complex TB pathology. We used these findings to predict a MMP/TIMP balance in active TB and confirmed this in human plasma, revealing the potential of MMP/TIMP levels as key components of a diagnostic matrix aimed at distinguishing active from latent TB (PPV = 92.9%, 95% CI 66.1-99.8%, NPV = 85.6%; 95% CI 77.0-91.9%). © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Source


Pazhanimurugan R.,Periyar University | Gopikrishnan V.,Periyar University | Shanmuga Sundaram T.,Periyar University | Radhakrishnan M.,National Institute for Research in Tuberculosis NIRT | Balagurunathan R.,Periyar University
Journal of Applied Pharmaceutical Science | Year: 2012

The present investigation was focused to study the antagonistic potential of actinobacterial strain TK2 isolated from Thirukurungudi Hills (Western Ghats, Tamil Nadu), against selected drug resistant bacterial pathogens. Of the 9 clinical bacterial strains, S. aureus was found to be resistant against methicillin and vancomycin while the remaining 8 gram negative pathogens were confirmed as extended spectrum beta lactamase (ESBL) producers. Strain TK2 showed good antagonistic activity against all the bacterial pathogens, except the three isolates of P. aeruginosa. Strain TK2 produced the antimicrobial activity on 4th day of incubation when growing on ISP2 agar medium whereas the same strain showed activity only on 8th day of incubation when it was grown on ISP2 broth. Of the various solvents tested for extraction, bioactive compound was extracted only in ethyl acetate. The crude extract showed 14-18 mm inhibition zone in disc diffusion method. The crude extract produced two spots in thin layer chromatography (TLC) in chloroform: methanol (30:60) solvent system. In bioautography, the second spot (Rf value 0.685) showed activity. The active compound was purified by preparative TLC, which showed maximum activity (15-20 mm inhibition) against test pathogens. Based on the results of chemical screening, the active compound was identified as sugar containing substance. Strain TK2 showed good growth on various growth media and culture conditions. Based on the studied phenotypic characteristics strain TK2 was identified as the species of the genus Streptomyces. Of the various growth parameters tested, ISP2 medium, glucose, pH 7, 1% NaCl and temperature 300C was influenced the antagonistic activity of strain TK2. Strain TK2 will be a potential for the isolation of bioactive compound(s) which will be a candidate for the development of antibiotic against drug resistant bacterial pathogens. Source


Dinesh S.,University of Madras | Menon T.,University of Madras | Hanna L.E.,National Institute for Research in Tuberculosis NIRT | Suresh V.,Annamalai University | And 2 more authors.
International Journal of Biological Macromolecules | Year: 2016

Sargassum swartzii, a marine brown algae with wide range of biological properties belongs to the family Sargassaceae. Bioactive fucoidan fractions (CFF, FF1 and FF2) were isolated from S. swartzii and characterized by linear gradient anion-exchange chromatography and FT-IR. The characterized fucoidan fractions contained mainly sugars, sulfate and uronic acid. In the present study, anti-HIV-1 property of the fucoidan fractions was investigated. Fraction FF2 was found to exhibit significant anti-HIV-1 activity at concentrations of 1.56 and 6.25 μg/ml as observed by >50% reduction in HIV-1 p24 antigen levels and reverse transcriptase activity. Fucoidan fractions have no cytotoxic effects on PBMCs at the concentration range of 1.56-1000 μg/ml. These results suggest that fucoidan fractions could have inhibitory activity against HIV and has potential as an anti-HIV-1 agent. © 2015 Elsevier B.V. Source


Narender M.,Kakatiya University | Jaswanth S.B.,Kakatiya University | Umadevi K.R.,National Institute for Research in Tuberculosis NIRT | Dusthackeer A.V.N.,National Institute for Research in Tuberculosis NIRT | And 2 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2016

Development of multidrug resistant (MDR) and extensively drug resistant (XDR) tuberculosis (TB) has been considered as major health burden, globally. In order to develop novel, potential molecules against drug resistant TB, twenty two (22) new 3-substituted-7-benzyl-5,6,7,8-tetrahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4(3H)-one (6a-k) and 3-substituted-7-benzyl-2-methyl-5,6,7,8-tetrahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4(3H)-one (7a-k) derivatives were designed and synthesized by using appropriate synthetic protocols. Pantothenate synthetase (PS) was considered as the target for the molecular docking studies and evaluated the binding pattern at active site, as PS plays a significant role in the biosynthesis of pantothenate in Mycobacterium tuberculosis (MTB). The preliminary in vitro antibacterial screening of test compounds was carried out against two strains of Gram-positive (Bacillus subtilis and Staphylococcus aureus) and Gram-negative (Escherichia coli and Klebsiella pneumoniae) bacteria. The antimycobacterial screening was performed against MTB H37Rv and an isoniazid-resistant clinical isolate of MTB. The compounds 6b, 6c, 6d, 6k, 7b, 7c, 7d and 7k exhibited promising antibacterial activity MIC in the range of 15-73 μM against all bacterial strains used and compounds 6d and 7b showed antimycobacterial activity (IC50<340 μM in LRP assay) and (MIC <9 μM in broth microdilution method). © 2016 Published by Elsevier Ltd. Source


Narender M.,Kakatiya University | Jaswanth S. B.,Kakatiya University | Umadevi K.R.,National Institute for Research in Tuberculosis NIRT | Dusthackeer A.V.N.,National Institute for Research in Tuberculosis NIRT | And 2 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2015

Development of multidrug resistant (MDR) and extensively drug resistant (XDR) tuberculosis (TB) has been considered as major health burden, globally. In order to develop novel, potential molecules against drug resistant TB, twenty two (22) new 3-substituted-7-benzyl-5,6,7,8-tetrahydropyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4(3H)-one (6a-k) and 3-substituted-7-benzyl-2-methyl-5,6,7,8-tetrahydropyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4(3H)-one (7a-k) derivatives were designed and synthesized by using appropriate synthetic protocols. Pantothenate synthetase (PS) was considered as the target for the molecular docking studies and evaluated the binding pattern at active site, as PS plays a significant role in the biosynthesis of pantothenate in Mycobacterium tuberculosis (MTB). The preliminary in vitro antibacterial screening of test compounds was carried out against two strains of Gram-positive (Bacillus subtilis and Staphylococcus aureus) and Gram-negative (Escherichia coli and Klebsiella pneumoniae) bacteria. The antimycobacterial screening was performed against MTB H37Rv and an isoniazid-resistant clinical isolate of MTB. The compounds 6b, 6c, 6d, 6k, 7b, 7c, 7d and 7k exhibited promising antibacterial activity MIC in the range of 15-73μM against all bacterial strains used and compounds 6d and 7b showed antimycobacterial activity (IC50 <340μM in LRP assay) and (MIC <9μM in broth microdilution method). © 2015. Source

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