People : Scientific : Faculty & Scientists

DR. NISHEETH AGARWAL, Ph.D. 

Associate Professor
+91-129-2876304  (09810390746)
nisheeth [at] thsti [dot] res [dot] in
Ph.D.
2015-present: Associate Professor, THSTI, Faridabad.
2010-2015: Assistant Professor, THSTI, Faridabad.
2005-2010: Postdoctoral Fellowship, Centre for Tuberculosis Research, Johns Hopkins University, Baltimore (USA)
2004-2005: Provisional Research Associate, Department of Biochemistry, Delhi University, India
1999-2004: Ph.D. (Biochemistry), Department of Biochemistry, University of Delhi South Campus, New Delhi
1997-1999: M.Sc. Biotechnology), School of Biotechnology, Banaras Hindu University, Varanasi

A. Research specialization:

Regulation of gene expression in M. tuberculosis; emergence of persistence and drug-resistance in M. tuberculosis; mycobacterial pathogenesis; host-pathogen interaction; host response to mycobacterial infection.

Ph.D. (2004): “Transcriptional machinery of mycobacteria: analysis of components” Department of Biochemistry, Delhi University, Delhi.

 

B. Major areas of research:

1.   Identification and characterization of new drug targets

2.   Understanding the mechanisms of drug-induced phenotypic tolerance and genetic resistance in M. tuberculosis

3.   Host response to M. tuberculosis infection

 

Published Papers: (18)

Cumulative citations:643; h-index: 10, i10 index: 11

2017

  • Khundrakpam Herojit Singh, Bhavya Jha, Abhisek Dwivedy, Eira Choudhary, Arpitha G N, Anam Ashraf, Divya Arora, Nisheeth Agarwal and Bichitra Kumar Biswal (2017) Characterization of a secretory hydrolase from Mycobacterium tuberculosis sheds critical insight into host lipid utilization by M. tuberculosis. J. Biol. Chem. (In press)

2016

  • Preeti Thakur, Nagavara Prasad Gantasala, Eira Choudhary, Nirpendra Singh, Malik Zainul Abdin and Nisheeth Agarwal (2016) The preprotein translocase YidC controls respiratory metabolism in Mycobacterium tuberculosis. Sci. Rep. 6, 24998; doi: 10.1038/srep24998.

  • Eira Choudhary, Ajitesh Lunge and Nisheeth Agarwal (2016) Strategies of gene inactivation in mycobacteria: achievements and challenges. Tuberculosis. 98:132-8. doi: 10.1016/j.tube.2016.03.005.

2015

  • Eira Choudhary, Preeti Thakur, Madhu Pareek and Nisheeth Agarwal. (2015) Gene silencing by CRISPR interference in mycobacteria. Nat. Commun. 6:6267 doi: 10.1038/ncomms7267.

2014

  • Eira Choudhary, William Bishai and Nisheeth Agarwal. (2014) Expression of a subset of heat stress induced genes of Mycobacterium tuberculosis is regulated by 3',5'-Cyclic AMP. PLoS ONE. 9(2): e89759.

2012

  • Christer Larsson, Brian Luna, Nicole C. Ammerman, Mamoudou Maiga, Nisheeth Agarwal, William R. Bishai. (2012) Gene expression of Mycobacterium tuberculosis putative transcription factors whiB1-7 in redox environments. PLoS ONE 7(7):e37516.

  • Nisheeth Agarwal, Madhu Pareek, Preeti Thakur and Vibha Pathak. (2012) Functional characterization of EngAMS, a P-loop GTPase of Mycobacterium smegmatis. PLoS ONE 7(4) e34571.
  • Mamoudou Maiga*, Nisheeth Agarwal*, Nicole C. Ammerman, Radhika Gupta, Haidan Guo, Mariama C. Maiga, Shichun Lun, William R. Bishai. (2012) Successful shortening of tuberculosis treatment using adjuvant host-directed therapy with FDA-approved phosphodiesterase inhibitors. PLoS ONE 7(2): e30749. *Equal contributions.

2010

  • Nisheeth Agarwal and William R. Bishai (2010) Subversion from the sidelines. Science 327(5964):417-8.

2009

  • Nisheeth Agarwal, Gyanu Lamichhane, Radhika Gupta, Scott Nolan, and William R. Bishai. (2009) cAMP intoxication of macrophages by a Mycobacterium tuberculosis adenylate cyclase. Nature 460: 98-102.
  • Nisheeth Agarwal and William R. Bishai (2009) cAMP signaling in Mycobacterium tuberculosis. Indian J Exp Biol. 47: 393-400.

2007

  • Nisheeth Agarwal, Samuel C. Woolwine, Sandeep Tyagi and William R. Bishai. (2007) Characterization of the Mycobacterium tuberculosis sigma factor SigM by assessment of virulence and identification of SigM-dependent genes. Infect Immun. 75: 452-61.

2006

  • Nisheeth Agarwal and Anil K. Tyagi. (2006) Mycobacterial transcriptional signals: Requirements for recognition by RNA polymerase and optimal transcriptional activity. Nucleic Acids Res. 34(15): 4245-4257.
  • Nisheeth Agarwal, Tirumalai R. Raghunand and William R. Bishai. (2006) Regulation of the expression of whiB1 in Mycobacterium tuberculosis: role of cAMP receptor protein. Microbiology 152: 2749-2756.
  • Deborah E. Geiman, Tirumalai R. Raghunand, Nisheeth Agarwal, and William R. Bishai. (2006) Differential gene expression in response to exposure to antimycobacterial agents and other stress conditions among seven Mycobacterium tuberculosis whiB-like genes. Antimicrob. Agents Chemother. 50: 2836-2841.

2003

  • Nisheeth Agarwal and Anil K. Tyagi. (2003) Role of 5’-TGN-3’ motif in the interaction of mycobacterial RNA polymerase with a promoter of ‘extended –10 class’. FEMS Microbiol. Lett. 225: 75-83.

2001

  • Anjali Tikoo, A.K. Tripathi, S.C. Verma, N. Agrawal and Gopal Nath. (2001) Application of PCR fingerprinting techniques for identification and discrimination of Salmonella isolates. Curr. Science 80: 1049-1052.

1999

  • C.K.M. Tripathi, Amrita Gupta, N. Agarwal, S.C. Tripathi, S.C. Agarwal and Vinod Bihari. (1999) Production of antibacterial metabolites by actinomycetes screened from natural environment. In Fermentation Biotechnology-Industrial Perspectives. (eds. S. Chand and S.C. Jain) pp. 295-299.
  • C.K.M. Tripathi, A. Gupta, N. Agarwal, S.C. Tripathi, S.C. Agarwal and Vinod Bihari. (1999) Production of antibacterial metabolites by actinomycetes screened from natural environment. In Fermentation Biotechnology-Industrial Perspectives. (eds. S. Chand and S.C. Jain) pp. 295-299.

A. Research Projects carried out as PI:5

Completed Research project: (1)

  • Toward the characterization of multiple P-loop GTPases in mycobacteria. (2011-14; Funded by Department of Biotechnology)

There are several known examples of chemical inhibitors which target essential metabolic pathways of pathogenic mycobacteria such as transcription (RNA polymerase inhibitor, rifampicin), DNA replication (fluoroquinolones such as moxifloxacin inhibiting DNA gyrase) and energy metabolism (a diarylquinolone, R207910 inhibiting ATP synthase), and have been proven highly effective in controlling M. tuberculosis infection to humans. However, due to emergence of multi drug- and extensively drug resistant strains of M. tuberculosis, there is an increasing demand to expand molecular drug targets. This project was aimed at characterization of a group of proteins which belong to GTPase superfamily in mycobacteria. Here, we studied the function and mode of action of a P-loop GTPases in mycobacteria, namely EngA. Our study indicated that EngA is a ribosomal protein which controls the assembly of 50S subunit and is thus indispensable for in vitro growth of mycobacteria. The study established future exploration of EngA and related GTPases as novel drug targets for screening of small molecule inhibitors.

Ongoing Research Projects: (2)

  • A systems approach to analyze changes in global phosphorylation status of proteins in macrophages infected with Mycobacterium tuberculosis complex bacteria, and their repercussions on mycobacterial virulence. (2014-2018; Funded by Department of Biotechnology)

The fact that globally ~9 million individuals are infected every year with M. tuberculosis has drawn a serious attention worldwide. Annually ~2 million people are dying due to the disease TB, and one third of world’s population is asymptomatically infected with this pathogen. With several thousand years of its stay in human body, M. tuberculosis has well adapted itself to successfully face the innate and adaptive immune responses of the host. This is primarily evident by the ability of the pathogen to restrict fusion of mycobacterial phagosomes with lysosomes within infected macrophages, and to undergo persistence under the influence of a combination of drugs. Hence, to survive these onslaughts M. tuberculosis must have devised mechanisms to manipulate the host signaling which will eventually allow its replication in phagosome.

In this project we are conducting a comprehensive study of the effect of mycobacterial infection on global phosphorylation status of the host proteome and their consequences on survival of bacteria in the host macrophages. Our objective is to identify previously uncharacterized phosphoproteins that respond specifically to M. tuberculosis infection and could serve as important determinants of infection. The information obtained from the proposed study can be further utilized in designing inhibitors that will target the pathways required for intracellular survival of bacteria, as well as identifying signatures of protection against M. tuberculosis infection in humans.

  • In vivocharacterization of the role of DNA gyrase in M. tuberculosis (Intramural support)

Genes encoding DNA topoisomerase, a ubiquitous enzyme involved in maintaining the integrity of chromosome during DNA replication, transcription and recombination, are strictly essential for bacterial survival. In Mycobacterium two classes of DNA topoisomerases are known: Topo I and Topo II (also known as DNA gyrase), as against E. coli where an additional enzyme Topo IV is also annotated. The mycobacterial DNA gyrase constitutes two subunits viz. GyrA and GyrB which exist as A2B2 complex. Since DNA Gyrase is the only enzyme in M. tuberculosis which is solely responsible for maintaining supercoiling, catenation and other related functions, it becomes vital for bacteria to strictly regulate the intracellular activity of this enzyme which may also involve accessory proteins in vivo.

This project revolves around understanding the function of DNA gyrase in vivo by using the conditional knockdown mutant strain of M. tuberculosis. Here, we propose to examine the effect of silencing of DNA gyrase on transcriptional and metabolic profiles of the pathogen and its susceptibility to different stresses and antibiotics.

Accept Research Project: (1)

  • Understanding the roles of ClpX and ClpC1 components of Clp proteolytic machinery in Mycobacterium tuberculosis (2018-2021; Funded by Department of Biotechnology)

Proteostasis is critical in any pathogen which has to sustain under hostile conditions. Majority of protein turnover in M. tuberculosis is regulated by an essential caseinolytic protease (Clp) which involves an ATPase and a proteolytic chamber (ClpP) to detoxify the effects of unfolded and dysfunctional proteins’ accumulation. Although role of ClpP is well characterized, specific functions of ATPase subunits (ClpX and ClpC1) in regulated proteolysis and underlying mechanisms of ClpP protease remains to identify in M. tuberculosis. In this project we study distinct roles of the ClpX and the ClpC1 subunits in regulated proteolysis in M. tuberculosis. In addition, we also propose to establish and perform in vitro biochemical assays for selective degradation of Clp substrate proteins of M. tuberculosis for future screening of small molecule inhibitors.

Research Project under review: (1)

  • Improvisation of CRISPR/Cas9 and CRISPRi-based approaches and their application in Mycobacterium tuberculosis gene manipulation to assist ongoing TB research and drug discovery programs in India (2017, Department of Biotechnology)

Intensive programs for development of new preventive and/or treatment interventions to control the number of tuberculosis (TB) cases are being pursued by various R&D organizations in India. In this context, gene specific knockout/knockdown is the most effective approach to understand bacterial genome to find new targets for drug discovery. Absence of the effective means to disrupt a gene in M. tuberculosis remains a big bottleneck. Existing methods of gene manipulation in Mtb are complex and inefficient. My research group at THSTI pioneered the use of an amenable CRISPRi tool for silencing genes in mycobacteria. With a vision to complement India’s various R&D programs against TB, we at THSTI & scientists from CSIR-IMTECH together propose to a) improve and establish the in-house CRISPR/Cas9-based gene editing strategies in M. tuberculosis, and b) implement the in-house tools to create a collection of mutants targeting essential genes in M. tuberculosis to leverage and dispense its advantages to the entire TB research community in the country.

 

B. Research Projects carried out as Co-PI:4 (Carried out with Dr. Ramandeep Singh, Associate Professor at THSTI)

Completed Research Project: (2)

  • Understanding the role of polyphosphate kinases and polyphosphatases in physiology of M. tuberculosis (2012-2015; Funded by Department of Biotechnology)
  • Investigating the role of MazF toxins in persistence and pathogenesis of M. tuberculosis (2011-2014; Funded by Department of Biotechnology)

Ongoing Research Project: (1)

  • Investigating the role of citrate lyases in physiology and persistence of M. tuberculosis. (2015-2018; Funded by Department of Biotechnology)

               Research Project under review: (1)

  • Targeting inorganic polyphosphate metabolism pathways to design better intervention against M. tuberculosis (2017, Department of Biotechnology)

Fellowships and awards:

2005-2010:         Postdoctoral Fellowship to conduct research in Center for TB Research at the Johns Hopkins University, USA

2009:                  Arthur M. Dannenberg Award for Tuberculosis Research at the Center for Tuberculosis Research, Johns Hopkins University.

1999-2004:         Junior and senior research fellowships by Council of Scientific and Industrial Research, India

1997-1999:         DBT Fellowship to pursue Master’s degree at the School of Biotechnology, Banaras Hindu University, Varanasi

A. Invited presentations to peer-reviewed, internationally established conferences/meetings:

1.   Guest/invited Lectures:

  • Jawaharlal Nehru University, New Delhi, November 2017
  • Delhi University, New Delhi, September 2017
  • KIIT University, Bhubaneswar, Odisha, Feb 2017
  • All India Institute of Medical Sciences, New Delhi, Oct 2016
  • University of Delhi South Campus, New Delhi, March 2016
  • All India Institute of Medical Sciences, New Delhi, 2015
  • University of California at Berkeley, USA, July 2012

 

2.   Conferences & Symposia attended/organized:

  • 5th Global Forum meeting on TB vaccine, New Delhi, February 2018 (Scheduled)
  • ImTechCon: Industry-Academia meet, Chandigarh, October 2017
  • XV Genetics Congress Trust, NASc complex, New Delhi, 23 November, 2016
  • EMBO Conference Tuberculosis 2016, Paris, 19-23 September 2016
  • ICMR - NIAID Joint Symposium on “Advancing the Tuberculosis Vaccine Agenda in India and Beyond”, NIRT, Chennai, 08-09 February 2016
  • Keystone symposium on “Tuberculosis: Understanding the Enemy (X8)”, Whistler, Canada, 13-18 March 2013

 

B. Major collaborations:

  • University of Antioquia, Colombia: Dr. Andres Baena Garcia     
  • UMR1173 INSERM - Versailles St Quentin University, France: Dr. Jean-Louis Herrmann
  • National Institute of Immunology (NII), India: Dr. Bichitra Biswal      
  • Colorado State University, USA: Dr. Nicole Kruh-Garcia  
  • Colorado State University, USA: Dr. Sebabrata Mahapatra        
  • All India Institute of Medical Sciences, India: Dr. Jaya Tyagi    
  • South Asian University, India: Dr. Preeti Saxena   
  • Delhi University, India: Dr. Yogendra Singh
  • Jawaharlal Nehru University, India: Dr. Gobardhan Das
  • Institute of Microbial technology, India: Dr. Alka Rao

 

C. Referee/Ad-hoc reviewer:

Editorial board member in JGAR (Journal of Global Antimicrobial Resistance, Elsevier press) since 2012; reviewer for several international and national journals such as Scientific Reports, PLoS One, Frontiers in Microbiology, Bioorganic and Medicinal Chemistry Letters; Examiner for many thesis reports from research institutions in India; Reviewer of research proposals submitted to various funding agencies in India.

 

D. Membership:

Life member of the Society of Biological Chemists, India

 

E. Contribution to the Academic and Administrative activities at the institution (THSTI):

  • THSTI-JNU Academic Committee member (2017-2020)
  • Chairperson of the Selection Committee for the post of Section Officer (Stores & Purchase) (2017)
  • Member of the Environmental Health and Safety Committee, THSTI (2017-2020)
  • Member of the Committee for deciding job responsibilities of STOs and TOs at THSTI (2017)
  • Chairperson of the Institutional Biosafety Committee, THSTI (2016-2019)
  • Member of the Institutional Biosafety Committee, THSTI (2012-2016)
  • Chairperson of the Local Purchase Committee, THSTI (2016-2019)
  • Organizing Committee member for the 5th Global Forum meeting in New Delhi (2016-2018)
  • DBT nominee for the Institutional Biosafety Committee at the India Innovation Center, New Delhi (2016-present)
  • Member of the Expert Screening Committee for Technology Licensing, THSTI (2016)
  • External member of the technical committee for establishment of ESI LC MS facility at Advanced Technology Platform Center, NCR Biotech Science Cluster, Faridabad (2016)
  • Member of the Committee for review of items covered under the Defect Liability: Phase I of the Construction of NCR-Biotech Science Cluster (2016)
  • Chairperson of the Sub-committee for Security arrangements, THSTI (2015-present)
  • PIO of the RTI Committee, THSTI (2014-2015)
  • Special invitee to attend The Programme Advisory Committee (PAC) at the Regional Center for Biotechnology, Faridabad (Sep 2015)
  • Member of the selection committee for the post of Professional Expert (Scientific Communication & PR), THSTI (Jun, 2015)
  • Member of the Selection Committee for Vaccine Research Innovation (VRI) Awardee, THSTI (Apr, 2015)

Supervision of graduate students, trainees and research fellows:

PhD supervised: 1

2010-2016:          Dr. Preeti Thakur

PhD registered currently: 2

2012-present:       Ms. Eira Choudhary

2014-present:       Dr. Ajitesh Lunge

Trainees and Research Fellows: 12

2010-present:       Mr. Saqib Kidwai, Technical officer

2010:                    Ms. Vibha Pathak, Summer trainee

2010-2011:           Mr. Uday Kumar, SRF (Project)

2014-2015:           Ms. Sandhya Galidevara, SRF (Project)

2016-2016:           Ms. Sangeeta Dutta, SRF (Project)

2017-present:       Ms. Upasna Madan, JRF (Project)

2017 (Jul-Aug):     Ms. Pramila Pal (PhD rotation)

2017 (Jul-Aug):     Mohd. Ilyas (PhD rotation)

2017 (Sep-Oct):    Ms. Nikita Aggarwal (PhD rotation)

2017 (Sep-Oct):    Mr. Saurabh Chugh (PhD rotation)

2017 (Nov-Dec):   Mr. Rohit Verma (PhD rotation)

2017 (Nov-Dec):   Mr. Surendra Prajapat (PhD rotation)