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Research Scientist SRI International
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Name: Sidharth Chopra, Ph.D.2008-present: Research Scientist at Centre for Infectious disease and Biodefense Research, Stanford Research Institute International, USAAbout Stanford Research Institute International: www.sri.comSRI International is an independent, non-profit research institute conducting client-sponsored research and development for government agencies, commercial businesses, foundations, and other organizations. SRI also brings its innovations to the marketplace by licensing its intellectual property and creating new ventures.For 65 years, since our beginnings when we were called, our strengths have been our staff's world-leading expertise and passion for working with clients on important challenges. SRI is well known for its legacy of innovations in communications and networks, computing, economic development and science and technology policy, education, energy and the environment, engineering systems, pharmaceuticals and health sciences, homeland security and national defense, materials and structures, and robotics.My current responsibilities include 1. Project leader of anti-tuberculosis drug screening National Institutes of Health (NIH) contractSupervise day to day activities involving screening of novel chemical entities (NCE’s) from various submitters world-wide as a part of $56.7 million NIH contract. The project work involves designing and conducting research experiments in the BSL-3 labs with drug-resistant Mycobacterium tuberculosis patient isolates. Among the experiments conducted include minimum inhibitory concentration (MIC) and bactericidal (MBC) determination, MIC against single and multiple drug-resistant strains and further pre-clinical microbiology development using High thorugh put Resazurin microtitre plate assay (REMA). We typically handle around ~30,000 compounds per year. This project is currently funded by NIH grant totaling $1.5 million US dollars. Hyperlink: http://www.sri.com/news/releases/091508.html2. Understanding the mechanisms of antibiotic resistance generation in M. tuberculosis and A. baumannii An important focus is to understand the generation of antibiotic resistance in M. tuberculosis and A. baumannii. We are utilizing whole scale genomics and proteomic techniques on syngenic bacterial strains to unravel the step by step mechanism responsible for generating antibiotic resistant bacteria. The final aim of the project is to identify novel therapeutic targets for targeting drug-resistant bacteria. This project is currently funded by Internal Research & Development (IR&D) grants from SRI International totaling $125,000.3. Drug-repurposing efforts to identify new indications for FDA-approved drugs against multi-drug resistant pathogens such as A. baumannii, M. abscessus and M. chelonae.Drug-resistant bacteria are on the rise while antimicrobial therapies to combat them are on the decline owing to pharmaceutical apathy. The drug-repurposing effort was initiated to identify drugs targeting nosocomial pathogens such as A. baumannii and emerging mycobacterial infections such as those caused by M. abscessus and M. chelonae. The currently approved therapy for A. baumannii is severely limited by increasing drug resistance whereas conventional approved chemotherapy for infections such as that caused by M. abscessus and M. chelonae does not guarantee eradication of infection from the host. For A. baumannii, we have identified tyrothricin as being highly potent against several drug-resistant clinical isolates. This is the first ever reporting of activity against gram-negative bacteria being demonstrated by Tyrothricin as it is usually used to treat S. aureus. Experiments to further characterize the drug target are currently underway.This project is currently funded by Internal Research & Development (IR&D) grants from SRI International totaling $35,000.4. Developing low cost, non invasive novel diagnostics for detection of Mycobacterium tuberculosis We are currently utilizing DNA aptamers to recognize Lipoarabinomannan (LAM), one of the most promising mycobacterial antigens for non invasive novel diagnostics. The DNA aptamers display the same affinity to their targets as antibodies while exhibiting temperature insensitivities. The technique utilized is SELEX for generating a variable library of DNA aptamers, followed by selection against LAM and further purification, thus generating the most promising aptamer. As of this time, we are suffering from indistinct background binding and low sensitivity by using the currently isolated aptamers. Further efforts to modify the selection procedure are currently being developed.This project is currently funded by Internal Research & Development (IR&D) grants from SRI International totaling $10,000.5. Identification of mycobacterium proteasome inhibitors using a novel luciferase assay In close collaboration with Stanford University, we have initiated a Medium through-put screen for identifying mycobacterial proteasome inhibitors using a novel luciferase assay. The proteasome has been identified as a promising drug target, especially during the latent infection.This project is currently funded by NIH/Stanford University grants totaling $30,000.2004-08 Postdoctoral Scientist at Stanford University with Prof. Gary Schoolnik, USAExtensive drug development work with evaluation and identification of novel Plectasin based antimicrobial peptides and their derivatives as drug candidates against Multi-drug Resistant (MDR) Mycobacterium tuberculosis and other pathogenic non tubercular mycobacteria (NTM’s) such as M. abscessus and M. kansasii was carried out in close collaboration with Dr. Hans-Henrik Kristensen, Senior Manager, Anti-Infective Unit, Novozymes A/S, Denmark.The research included1. Novel methods such as bacterial luciferase expressing mycobacteria were developed to allow rapid High Throughput screening and identification of hit compounds from libraries of antimicrobial peptides. 2. These hit compounds were studied for their pattern of inhibitory activity against a large panel (~50+ strains) of globally diverse, clinical patient isolates 3. Efforts were made to identify patterns of resistance to the hit compounds leading to identification of cyclopropanated mycolic acids as being one of the resistance factors. 4. Based on identification of active compounds and concomitant Structure Activity Relation (SAR) studies, further screening of variant libraries was done to identify even better hit compounds. 5. On the basis of Dr. Chopra’s findings, Novozymes was awarded US patent entitled “Use of defensin against Tuberculosis” U.S. patent application no. PCT/EP2009/0524056. Novozymes additionally established a scientific collaboration with AstraZeneca Research and Development group in Bangalore, India which plans to carry out pre-clinical development and animal model efficacy studies. 2000-04 Doctorate topic: Mycobacterium tuberculosis Aspartate decarboxylase and development of strategies for selection of inhibitors for protein targetsOne aspect of my doctorate project focused on complete biochemical and structural characterization of Aspartate decarboxylase from Mycobacterium tuberculosis (Mtb). The crystal structure of the Aspartate decarboxylase was solved at 2.99 Å in close collaboration with Dr. K. Swaminathan, National University of Singapore to validate this target and perform targeted drug design.The other aspect of my doctoral thesis involved the development of a novel method named “Codon Shuffling” for evolving proteins in vitro. In developing this method, we employed a molecular approach for generating a multitude of structurally diverse yet functionally similar proteins that have all “evolved” from the parent enzyme.
2008-Present: Research Scientist, Centre for Infectious disease and Biodefense Research Stanford Research Institute International2004-2008: Postdoctoral fellow–Microbiology and Immunology, Stanford University School of Medicine, Professor Gary K. Schoolnik, Advisor2000–2004: Ph.D. in Microbiology / Biotechnology, International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi, India. Dr. Anand Ranganathan, Advisor1997-1999: Master of Science in Microbiology, Major in Microbiology, Panjab University, Chandigarh, India1994-1997: Bachelor of Science in Microbiology, University of Delhi, New Delhi, India
1. Microbiology with focus on Infectious diseases, special emphasis on Mycobacterium species including Non tubercular mycobacteria2. Molecular Mycobacteriology including Gene knockouts, Over-expression, Transposon Mutagenesis, TRASH analysis, antimicrobial susceptibility determination using MGIT. 3. Microbial physiology4. Microarray design and data analysis5. PCR based technologies6. Protein expression and purification/interaction/bacterial two-hybrid system7. Cloning techniques and site directed mutagenesis8. Basic biochemistry including enzyme activity assays
Peer Reviewed Publications:1. Kashyap DR, Vohra PK, Chopra S, Tewari R. Applications of pectinases in the commercial sector: A Review. Bioresource Technology. 2001 May; 77(3): 215-27. Citation Index: 252. Impact factor of Journal: 4.722. Chopra S, Singh SK, Sati SP, Ranganathan A, Sharma A. Expression, purification, crystallization and preliminary X-ray analysis of the acyl carrier protein synthase (acpS) from Mycobacterium tuberculosis. Acta Crystallographica (D) Biological Crystallography. 2002 Jan; 58 (Pt 1): 179-81.Citation Index: 5. Impact factor of Journal: 2.93. Chopra S, Pai H, Ranganathan A. Expression, purification, and biochemical characterization of Mycobacterium tuberculosis aspartate decarboxylase, PanD. Protein Expression & Purification. 2002 Aug; 25(3): 533-40.Citation Index: 15. Impact factor of Journal: 1.564. Chopra S, Ranganathan A. Protein evolution by "codon shuffling": a novel method for generating highly variant mutant libraries by assembly of hexamer DNA duplexes. Chemistry & Biology. 2003 Oct; 10 (10): 917-26.Citation Index: 18. Impact factor of Journal: 6.3735. Rao A, Chopra S*, Ram G, Gupta A, Ranganathan A. Application of the "codon-shuffling" method. Synthesis and selection of de novo proteins as antibacterials. Journal of Biological Chemistry. 2005 Jun 24; 280 (25): 23605-14. (* Equal contribution)Citation Index: 7. Impact factor of Journal: 7.3856. Gopalan G, Chopra S, Ranganathan A, Swaminathan K. Crystal structure of uncleaved L-aspartate-alpha-decarboxylase from Mycobacterium tuberculosis. Proteins. 2006, 65(4): 796-802.Citation Index: 4. Impact factor of Journal: 3.0857. Flores-Valdez and Sidharth Chopra. “Global reemergence of tuberculosis: Are host defense peptides an option to ameliorate disease burden?” Microbial drug resistance, 2010 Mar; 16(1):1-7.Citation Index:. Impact factor of Journal: 1.998. Chopra S, Torres-Ortiz M, Hokama L, Madrid P, Tanga M, Mortelmans K, Kodukula K, Galande AK. Repurposing FDA-approved drugs to combat drug-resistant Acinetobacter baumannii. J Antimicrob Chemother. 2010 Dec; 65(12):2598-601.Citation Index: 1. Impact factor of Journal: 4.359. Chopra S*, Matsuyama K, Hutson K and Madrid P. Identification of antimicrobial activities amongst FDA-approved drugs for combating Mycobacterium abscessus and Mycobacterium chelonae. Journal of Antimicrobial Chemotherapy. 2011 Jul; 66(7): 1533-6 (*First and corresponding author)Citation Index:1. Impact factor of Journal: 4.3510. Malabika Sarker, Sidharth Chopra, Kristien Mortelmans, Krishna Kodukula, Carolyn Talcott, and Amit K. Galande. In Silico Pathway Analysis Predicts Metabolites That Are Potential Antimicrobial Targets. Journal of Computer Science and System Biology. (DOI http://dx.doi.org/10.4172/jcsb.1000071)Citation Index: Impact factor of Journal: 2.811. Arlyn Tambo-ong, Sidharth Chopra, Bryan T. Glaser, Karen Matsuyama, Tran Tran and Peter B. Madrid. Mannich reaction derivatives of novobiocin with modulated physiochemical properties and their antibacterial activities. (Accepted for publication in Bioorganic & Medicinal Chemistry Letters), Article # BMCL-D-11-00810, 7 July, 2011.Citation Index: Impact factor of Journal: 2.712. Sidharth Chopra* and Amit Galande. A Fluoroquinolone-resistant Acinetobacter baumannii without the Quinolone Resistance-Determining Region Mutations. (Accepted for publication in Journal of Antimicrobial Chemotherapy) DOI: 10.1093/jac/DKR364, 2011. (* First and corresponding author).Citation Index:1. Impact factor of Journal: 4.35Peer Review of Manuscripts:1. Biomed Central Microbiology2. Journal of Antimicrobial Chemotherapy3. Drug Discovery Today4. PLoS One5. Journal of Infectious diseases6. PLoS Medicine7. International Journal of Tuberculosis and Lung Disease8. Molecular Microbiology9. Journal of Clinical Microbiology10. Antimicrobial and Agents Chemotherapy11. Journal of BacteriologyConferences and Posters:1. Sidharth Chopra and Anand Ranganathan. “Studies on L-Aspartate decarboxylase of Mycobacterium tuberculosis”. Poster presented at International Congress on Infectious diseases (ICID) held from March 11-14th, 2002 in Singapore.2. Sidharth Chopra and Anand Ranganathan. “L-Aspartate decarboxylase of Mycobacterium tuberculosis: a validated drug and vaccine target”. Poster presented at the First International Conference on “TB Vaccines for the World” held from 17-19th of September 2003 in Montreal, Canada.3. Gopalan Gayathri, Sidharth Chopra, Anand Ranganathan & K. Swaminathan. “Structural investigations of L-Aspartate decarboxylase from Mycobacterium tuberculosis”. Poster presented at Third International Conference on Structural Biology and Functional Genomics, Singapore, December 2-4, 2004.4. Alka Rao, Sidharth Chopra, Geeta Ram, Anand Ranganathan. “Synthesis And Selection of Antibacterials using Codon-Shuffling As Method For De Novo Protein Design”. Poster presented at 14th International Conference on Intelligent Systems for Molecular Biology, Fortaleza, Brazil, August 6-10, 2006.
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