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WELCOME TO THE 2011 - Harvard Initiative for Global Health ...

WELCOME TO THE 2011 - Harvard Initiative for Global Health ...

Methods Nine crude

Methods Nine crude extracts were obtained from roots, stems, leaves, and fruits of Chlorophytum macrophyllum, Solanum aculeastrum, Aframomum melegueta, Desmodium adscendens using maceration in methanol. These extracts were tested in vitro against Mycobacterium smegmatis MC2 using the Resazurin Microtiter Assay with serial drug concentrations of 50 to 0.05mg/mL. A phytochemical screening was conducted to determine the types of metabolites in the extracts. Results Two of the tested nine extracts from the fruits of Aframomum melegueta and Solanum aculeastrum showed significant potency, with Minimal Inhibitory Concentration of 5 mg/ml. Phytochemical screening revealed the presence of flavonoids, alkaloids, saponins, anthocyanins, terpenoids, sterols, resins, lipids, phenols, tannins and glycosides. Conclusion: The antimycobacterial activity of promising extracts supports the ethnomedicinal uses of associated plants as remedies for the treatment of tuberculosis and/or respiratory tract infections. The results obtained also support that these plants should be further investigated as sources of drugs against TB. Keywords: Crude extracts; Mycobacterium smegmatis; Phytochemical screening 29) CtpD is required for Mycobacterium tuberculosis pathogenesis Daniel Raimunda 1 , Teresita Padilla-Benavides 1 , Jarukit E. Long 2 , Christopher M. Sassetti 2,3 , and José M. Argüello 1 1 Department of Chemistry and Biochemistry, Worcester Polytechnic Institute, Worcester, MA., USA. 01609, 2 Department of Microbiology and Physiological Systems. University of Massachusetts Medical School. Worcester, MA., USA 01655, 3 Howard Hughes Medical Institute, Chevy Chase, Maryland, USA. 20815 Genetic studies in the tuberculosis mouse model have suggested that mycobacterial metal efflux systems, such as the P1B4-ATPase CtpD, are important for pathogenesis. Studies on M. smegmatis showed that CtpD is required for Co 2+ and Ni 2+ transport. A deletion mutant of ctpD showed decrease of growth fitness and intracellular metal accumulation in presence of Co 2+ and Ni 2+ . ATPase activity of an heterologously expressed and purified CtpD was stimulated in the presence of Co 2+ , Ni 2+ , and to a lesser extent Zn 2+ . Interestingly, M. tuberculosis also presents a paralogous gene, ctpJ. In order to assess the functional roles of these PIB4-ATPases, deletion mutants of ctpD (Rv1469) and ctpJ (Rv3473) were generated and their transcriptional induction and metal homeostasis were studied in parallel experiments. In H37Rv WT strain, transcription of both was up-regulated by various redox stressors, but only ctpJ was induced by Co 2+ . Accumulation of Co 2+ was observed in the ctpJ mutant strain while ctpD mutant showed a decrease in total Co 2+ content. Experiments in a mouse competition infection assay (single mutant vs. WT), showed that the ctpD deletion affected the survival rate in lungs. The phenotype was reverted by gene complementation. These observations suggests that in M. tuberculosis CtpD is required for virulence likely by loading Co 2+ , Ni 2+ or Zn 2+ to an extracellular metalloprotein necessary for overcoming stress conditions met in the macrophage phagosome. CtpJ would be required for efficient Co 2+ and Ni 2+ removal from the cytosol, a condition hardly met in the phagosome but probably present in other bacterial niche. This work was supported by NIH awards F32A1093049 (J.E.L.), 1R21AI082484 (J.M.A.), AI064282 (CMS) and the Howard Hughes Medical Institute (CMS). 30) DNA methylation regulates gene expression and enhances hypoxic survival of Mycobacterium tuberculosis Scarlet S. Shell 1 , Erin G. Prestwich 2 , Seung-Hun Baek 3 , Rupal R. Shah 1 , Christopher M. Sassetti 3 , Peter C. Dedon 2 , and Sarah M. Fortune 1 . 31

1 Department of Immunology and Infectious Diseases, Harvard School of Public Health, 2 Department of Biological Engineering and Center for Environmental Health Studies, Massachusetts Institute of Technology, 3 Department of Microbiology & Physiological Systems, University of Massachusetts Medical School. DNA methylation regulates gene expression in many organisms. In eukaryotes DNA methylation is associated with gene repression, while in the Proteobacteria DNA methylation exerts both activating and repressive effects on numerous genes through largely locus-specific mechanisms. Here we investigate the type, location and function of DNA methylation in M. tuberculosis. We show that the predominant DNA methyltransferase in the Euro-American lineage of M. tuberculosis is encoded by a gene we term mmt. Mmt creates N6-methyladenine in a six-basepair recognition sequence present in approximately 2,000 copies across the genome. Several genes have reduced expression when mmt is deleted. Each of these genes has an Mmt site located four or five basepairs upstream of its transcriptional start site and is affected by Mmt to a similar magnitude, suggesting that they Mmt may regulate their expression through a shared paradigm. While strains lacking mmt grow normally, they display reduced survival in hypoxic conditions, suggesting that methylation might promote survival in discrete host microenvironments. Surprisingly, M. tuberculosis strains of the Beijing lineage harbor a point mutation that largely inactivates Mmt, while they possess a second functional DNA methyltransferase that is inactivated in the Euro-American lineage. Our results indicate that Mmt regulates gene expression in M. tuberculosis and plays an important but strain-specific role in fitness during hypoxia. Supported by NIH grant 1F32AI085911-01A1 and by the Heiser Program for Research in Leprosy and Tuberculosis 31) Successful Implementation of an MDR-TB Treatment Program in Ethiopia Rocio Hurtado, Daniel Meressa, Ridwan Bushra, Bekele Fekade, Ermias Diro, Hanan Yusuf, Kasim Abato, Kristian Olson, Paritosh Prasad, Tewodros Daniel, Getachew Aderaye, Sok Thim, and Anne Goldfeld Global Health Committee and Harvard Medical School, Boston, MA, 02115 Background Ethiopia ranks seventh among the world’s 22 high-burden TB countries and has a large burden of MDRTB with an estimated 6000 new cases/year. Since February 2009, the Global Health Committee (GHC), in partnership with the Ethiopian Ministry of Health (MOH), has initiated and scaled up MDRTB treatment using a community-based model, adapted from the GHC’s prior program implementation of MDRTB care in Cambodia. This is the main mechanism for MDRTB treatment for the entire country. Methods Retrospective analysis of interim outcomes for patients enrolled in the Ethiopian GHC-MOH MDRTB treatment program between February 1, 2009 and April 24, 2012. Since August 2010, the program in Addis Ababa based at St. Peter’s Hospital expanded to include an additional enrollment site in Gondar (northern Ethiopia). Results Four hundred and forty-three (443) patients were enrolled in the cohort during this time frame: 52.6% male and 47.4% female. The median age was 27 years. All patients were tested for HIV, and 21.4% were noted to be co-infected. Eighty seven patients (87) have achieved cure or treatment completion; 306 patients are currently in treatment; 6 patients have defaulted and 44 patients have died. Fifty-one patients were initiated on therapy as outpatients. Conclusion Successful treatment implementation and scale-up of MDRTB care can be achieved with southto-south transfer of a community-based program such as the GHC-MOH partnership model outlined above. 32

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