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Rajesh Nagarajan, Ph.D.

Associate Professor

Biochemistry

Email: rajnagarajan@boisestate.edu

Office: SCNC 313

Phone: (208) 426-1423

Research Interests:

  • Antibiotic Resistance, Bacterial Virulence and Quorum Sensing
  • Enzymology / Antimicrobial Drug Discovery
  • Bioorganic Chemistry / Protein Biochemistry / Chemical Biology
  • Biomolecular NMR to investigate structure-function relationships in proteins

Undergraduate Research Assistant

What am I looking for in an undergraduate research assistant?

What courses would you recommend students have taken prior to working in your laboratory?

  • At least 2 semesters of General Chemistry (CHEM111 and CHEM112). Additionally at least a semester of organic chemistry or Introductory Biology is preferred.

How many hours per week do you expect a student to spend in the laboratory per research credit and does the time have to be a set schedule?

  • About 10 hours. Students can set their own work schedule.

Ideally, for what length of time would a student research in your laboratory to achieve a meaningful research experience?

  • A minimum of 2 semesters (1 year).

Educational Background

2004-2006: MD Postdoc | Johns Hopkins University, Baltimore

1998-2004: Ph.D. – Chemistry | Wesleyan University, Middletown, CT 

1996-1998: M.S. – Chemistry | Indian Institute of Technology, Chennai 

1993-1996: B.S. – Chemistry | Madras Christian College, Chennai, India

Research Overview

The rapid rise in multidrug resistant organisms pose special challenges to treating bacterial infections. Therefore, therapeutic strategies that combat bacterial virulence without aggravating drug resistance are in great demand. Since antibiotics threaten the survival of microorganisms, it puts selective pressure on bacteria to develop resistance. An alternative strategy to tackle this problem is to develop antivirulent drugs that limit bacteria’s ability to harm the host aka pathogenicity. Let us take a step back and ask a fundamental question: Is it possible for a single cell to impact the environment (good/bad)? The answer to this question is clearly ‘No’. If that is the case, then how could a bacterium harm (and in some cases benefit) a more complex, multicellular species such as humans? Our current understanding on bacterial behavior suggests that a bacterium could indeed have a social life that is facilitated by an interbacterial communication mechanism called quorum sensing.

Bacteria use a chemical language called autoinducers, (which are small diffusible signal molecules) to communicate with each other. In Gram-negative bacteria, the signals are N-acyl-homoserine lactones (AHL) whereas in Gram-positive species they are autoinducer peptides (AIP). Quorum sensing signals aka autoinducers are made by a dedicated set of enzymes called ‘I’ proteins inside the cell. As bacterial cells divide, the concentration of autoinducers in the environment increases proportionately until they reach a threshold concentration where they begin to diffuse away and bind to the receptors (also called as ‘R’ proteins; e.g., LuxR) of neighboring bacteria. The autoinducer bound receptors multimerize to expose DNA binding cavity that leads to the expression of genes responsible for synthesizing more of these autoinducers. Bacteria use these small molecules to take a census count of neighboring bacteria in the colony and hence this pathway is named as ‘Quorum Sensing’. Quorum sensing plays a major role in formation, development and maturation of biofilms in many pathogenic bacteria. Bacterial infections are very difficult to treat in this biofilm mode because a thick polysaccharide matrix encapsulates bacteria, protecting them from antibiotic attack. Therefore, quorum sensing inhibitors have emerged as an alternative and attractive strategy to treat bacterial infections by manipulating bacterial pathogenicity. In addition, QSI may also serve as useful probes to study social behavior in bacteria, which could increase our understanding on how resistance to antibiotics develops and spreads among bacteria.

Figure 1: Quorum Sensing Overview. The signal synthase is an attractive target to inhibit bacterial quorum sensing.

Several pathogenic bacteria including Pseudomonas aeruginosa, Yersinia pestis, Burkholderia pseudomallei etc. use AHL based quorum sensing to exhibit virulence. Small molecule inhibitors for AHL synthase enzymes hold significant promise as antimicrobials in treating multidrug resistant bacterial infections. However, our understanding on the mechanism of AHL synthesis remains poorly understood, which slows discovery of AHL synthase inhibitors.

Research Focus

We use a variety of tools including small molecule organic synthesis, protein biochemistry, enzymology, spectroscopy, structural biology, microbiology and bioinformatics to address mechanistic questions on signal synthesis. Specifically, we strive to learn how AHL synthases achieves fidelity in signal synthesis. Another aspect of our program focuses on inhibitor development for AHL synthases.

Select Publications (2018-2021)

Shi-Hui Dong, Mila Nhu Lam, Rajesh Nagarajan and Satish K. Nair. Structure. Structure-Guided Biochemical Analysis of Quorum Signal Synthase Specificities. ACS Chemical Biology (2020), 15, 1497-1504.

Julia Thomas Oxford, Rajesh Nagarajan et al. Center of Biomedical Research Excellence in Matrix Biology: Building Research Infrastructure, Supporting Young Researchers, and Fostering Collaboration. International Journal of Molecular Sciences (2020), 21(6), 2141.

Daniel Shin, Christoph Gorgulla, Michelle E. Boursier, Neilson Rexrode, Eric C. Brown, Haribabu Arthanari, Helen E. Blackwell and Rajesh Nagarajan. N-Acyl-Homoserine Lactone Analog Modulators of the Pseudomonas aeruginosa RhlI Quorum Sensing Signal Synthase. ACS Chemical Biology (2019), 14, 10, 2305-2314.

Daniel Shin and Rajesh Nagarajan. Enzymatic Assays to Investigate Acyl Homoserine Lactone Autoinducer Synthases. Methods in Molecular Biology (2018), 1673:161-176.

Mila Nhu Lam, Dastagiri Dudekula, Bri Durham, Noah Collingwood, Eric C. Brown, and Rajesh Nagarajan. Insights into beta ketoacyl-chain recognition for beta-ketoacyl-ACP utilizing enzymes. Chem Comm (2018), 54(64):8838-8841.

Michelle E. Boursier, Joseph D. Moore, Katherine N. Heitman, Sally P. Shepardson-Fungairino, Joshua B. Combs, Lea C. Koenig, Daniel Shin, Eric C. Brown, Rajesh Nagarajan and Helen E. Blackwell. Structure-Function Analyses of the N-Butanoyl-L-Homoserine Lactone Quorum-Sensing Signal Define Features Critical to Activity in RhlR. ACS Chemical Biology (2018), 13(9):2655-2662.

Select Grants (2018-2021)

8/1/2019 – 7/31/2022

  • Mechanistic Investigation on Carrier Protein Recognition in Quorum Sensing Synthases – National Science Foundation

Teaching Philosophy

Effective classroom teaching has unique challenges in the 21st century. Today’s students have so many career paths to choose from and often this has led to diverse interests among the student community. Even students with focused interests are faced with the daunting task of assimilating a plethora of new information. In this context, I visualize my role as a facilitator encouraging students to develop interest in the subject material and support them to understand the fundamentals of the subject instead of memorizing it. I always stress the point that earning a high grade and understanding the material goes hand-in-hand and it is often impossible to separate one from the other. I truly believe that independent thinking, not mere reiteration of facts will be critical for the success of a student in a competitive job market. As a teacher, I am committed to helping students meet these challenges and ultimately achieve their personal goals.

Teaching

CHEM111 General Chemistry I

CHEM112 General Chemistry II

CHEM301: Survey of Organic Chemistry

CHEM431: Biochemistry I

CHEM433: Biochemistry II

CHEM432: Biochemistry Laboratory

BIOCHEM512: Intermediary Metabolism

BIOCHEM513: Advanced Enzymology

BMOL605: Current Scientific Literature

BMOL602 Biomolecules II

Student Learning Opportunities

The projects in my laboratory are at the interface of chemistry and biology spanning the areas of organic chemistry, biochemistry and microbiology. The interdisciplinary nature of our research program will easily allow a student to work on a project with either a chemical or biochemical focus. Students working on our research projects will have the opportunity to learn one or more of these tools including small molecule organic synthesis, protein purification, enzyme assays, HPLC, UV-Visible spectroscopy, NMR spectroscopy (including biomolecular NMR), fluorescence spectroscopy, gel-electrophoresis and bioinformatics.