Staff Fellow — Division of Microbiology

Kuppan Gokulan, Ph.D.
(870) 543-7121
NCTRResearch@fda.hhs.gov  

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 About  |  Publications  |  Lab Member

Background

Dr. Kuppan Gokulan studied biochemistry and immunology at the All India Institute of Medical Sciences, New Delhi, India. His graduate research was primarily focused on peptide-based vaccine design against human immunodeficiency virus (HIV) and modulating immune response by linking immunomodulators with peptide antigens. In 2010 he joined FDA’s National Center for Toxicological Research (NCTR) as a commissioner’s fellow before working as an Oak Ridge Institute for Science and Education (ORISE) visiting scientist at NCTR from 2012 to 2015. Prior to this Dr. Gokulan was a research scientist at Texas A&M University (TAMU) in the Department of Biochemistry. Dr. Gokulan is currently a staff fellow in the Division of Microbiology at NCTR. He has extensive hands-on research experience in structural biology and in silico modeling which he uses to solve macromolecular structures with the potential for metabolic disease drug targets. In addition, Dr. Gokulan has used a structural biology approach to identify inhibitors against bacterial enzymes in drug- or multidrug-resistant bacteria by employing in silico information, protein homology modeling, and high-throughput drug screening against bacteria. 

Dr. Gokulan has been an adjunct faculty member in the Department of Physiology and Biophysics at the University of Arkansas for Medical Sciences (UAMS) since 2011. During the FDA Commissioner’s Fellow Program, he acquired extensive training in public policy, FDA rules, epidemiology, clinical trials, management of drug discovery, pharmacokinetics, pharmacodynamics, and toxicology. Dr. Gokulan has participated in and completed the New Reviewer, Investigational New Drug Regulations and Policies, and Lifecycle Approach training courses offered by FDA’s Center for Biologics Evaluation and Research and Center for Drug Evaluation and Research (CDER). He is actively involved in FDA’s priority research areas which are essential for regulatory guidance.

In 2014, Dr. Gokulan received an outstanding service award by NCTR for his research contribution in microbiome and host cell interaction. In 2015, he received a CDER grant to conduct research on “Nonclinical modeling and risk assessment of FDA-regulated drug-nanocrystals.” In addition, he is also co-principal investigator on NCTR projects that include the “Role of plasmid-encoded factors in Salmonella enterica virulence” and the “Effects of graphene-induced toxicity on the intestinal microbiota and gut-associated immune response using in-vitro model system.” Dr. Gokulan has several collaborative research projects with UAMS, TAMU, and the University of Connecticut in structure-based drug discovery and the cytotoxic effect of nanocrystal drugs in the gastrointestinal tract. 

Honors and Awards

• 2019 — NCTR/FDA Special Act Award for exemplary research in highlighting the importance of microbiomes in toxicity
• 2017 — NCTR group cash award for outstanding research and regulatory impacts by providing data to FDA’s Center for Veterinary Medicine on the effect of short and long-term exposure of residual levels of tetracycline in food on the intestinal microbiome
• 2017 — NCTR/FDA Special Act Award for contributions to “Tetracycline Residue and Microbiome Interaction”

Research Interests

Dr. Gokulan’s research falls under several priority research areas of NCTR and FDA and includes generating experimental data to support regulatory reviewers in the areas of:

1. The impact of transmissible plasmids on bacterial uptake, colonization, and host gene expression during the early stages of S. enterica Heidelberg infection
2. The molecular mechanism of drug and multi-drug bacteria
3. The effects of residual levels of antibiotics/xenobiotics on the barrier functions of human intestinal epithelial cells
4. The evaluation of the toxicity of nanocrystal drugs using nonclinical models and collaborating with CDER and the University of Connecticut to address critical problems

Dr. Gokulan’s lab also investigates knowledge-gaps associated with drug nanocrystals and their interaction with the gastrointestinal (GI) tract. Intestinal commensal bacteria play an essential role in maintaining healthy intestinal tissue, the shaping and development of immune response, and preventing the adverse effect of pathogenic bacteria. Currently, more than 750 clinical trials are in-progress involving potential nanomedicine products. Of these, 38 are approved products/currently in use and 128 are investigative new drug (IND) applications, of which 14% are drug nanocrystals. Approximately 82% of drug nanocrystal IND applications are for oral administration. For FDA regulatory/reviewer guidance, the agency needs experimental data to assess the effect of drug nanocrystals on the human GI tract.

Dr. Gokulan is seeking to understand how the bacterial cell-wall enzymes modify the peptidoglycan layers and cell-wall components in drug/multidrug-resistance bacteria by employing a protein homology modeling and drug-docking approach to address drug resistance. Expression of soluble protein is a prerequisite for functional characterization and drug screening for therapeutic proteins and antibodies, so he has established protein over-expression by using three different hosts’ expression systems. Recently he also developed a cell culture-based, high-throughput screening assay for drug discovery against antibiotic-resistant bacteria. Specifically, one of the bacterial cell-wall enzymes that is involved in peptidoglycan synthesis (L-D-Transpeptidase), which is responsible for antibiotic resistance in enzymes, over-expressed in E. coli. This over-expressed system mimics the drug-resistant bacteria.

Another major focus of research in Dr. Gokulan’s laboratory is to understand the early host immune response during bacterial invasion and how the bacterial pathogens alter the host immune-response genes via signaling pathways to establish bacterial colonization within the host. He is investigating the factors that lead to persistent bacterial infection, even when the host mounts an immune response against the bacterial insult, and how pathogenic microbes evade the immune response. He is addressing the antibacterial effects of the aloin, which has been used in dietary supplements, laxatives, weight loss supplements, beverages, beauty/cosmetics products, and vitamins, against intestinal commensal bacterial species. However, there is limited information available on the toxicity of these aloe products. The present study provides an evaluation of minimum inhibitory concentration (MIC) for the intestinal microbiota, which will help identify the acceptable dietary intake value for consumption of aloin/Aloe Vera in consumer products without altering the intestinal microbiome.

Dr. Gokulan has established a virulence and persistence assay to monitor Salmonella enterica Heidelberg-induced cell toxicity using macrophages and intestinal epithelial cells. He is also involved in identifying unique virulence genes and transmissible plasmids that contribute to antibiotic resistance in foodborne pathogens. Understanding the involvement of plasmid-encoded genes in antimicrobial resistance, colonization, invasion, and formation of the secretary apparatus will provide an improved knowledge of resistance and molecular mechanism of virulence-associated secretion by the bacterial type IV secretion system (T4SS). The outcome of the study will address several unresolved questions of bacterial pathogenesis and bacterial secretion systems.

Professional Societies/National and International Groups                                                         

American Society of Microbiology
Member
2012 – Present

Association of Clinical Biochemistry of India
Member
1994 – Present

FDA Immunology Working group
Member
2020 – 2021

FDA-National Institutes of Health-National Institute of Standards and Technology-U.S. Department of Agriculture Joint Agency Microbiome
Member
2018 – 2021

Indian Immunological Society
Member
1991 – Present

Nanocore Task Force
Member
2020 – 2021

Tuberculosis Structural Genomic Consortium
Member
2001 – Present
 

Selected Publications

Impact of Chronic Tetracycline Exposure on Human Intestinal Microbiota in a Continuous Flow Bioreactor Model.
Ahn Y., Jung J.Y., Kweon O., Veach B.T., Khare S., Gokulan K., Piñeiro S.A., and Cerniglia C.E.
Antibiotics. 2021, 10(8):886. doi: 10.3390/antibiotics10080886.

Co-Exposure to Boscalid and TiO2 (E171) or SiO2 (E551) Downregulates Cell Junction Gene Expression in Small Intestinal Epithelium Cellular Model and Increases Pesticide Translocation.
Cao X., Khare S., DeLoid G.M., Gokulan K., and Demokritou P.
NanoImpact. 2021, 22:100306. doi: 10.1016/j.impact.2021.100306 [Epub 2021 Mar 10].

Conformational Changes of the Receptor Binding Domain of SARS-CoV-2 Spike Protein and Prediction of a B-cell Antigenic Epitope Using Structural Data.
Khare S., Azevedo M., Parajuli P., and Gokulan K.
Front. Artif. Intell. 2021, 4:630955. doi: 10.3389/frai.2021.630955 [eCollection 2021].

Differential Toxicological Outcome of Corn Oil Exposure in Rats and Mice as Assessed by Microbial Composition, Epithelial Permeability and Ileal Mucosa Associated Immune Status.
Gokulan K., Kumar A., Lahiani H., Sutherland V., Cerniglia C.E., and Khare S.
Toxicological Sciences. 2021, 180(1):89-102. doi: 10.1093/toxsci/kfaa177.

Human Intestinal Tissue Explant Exposure to Silver Nanoparticles Reveals Sex Dependent Alterations in Inflammatory Responses and Epithelial Cell Permeability.
Gokulan K., Williams K., Orr S.E., and Khare S.
Int. J. Mol. Sci. 2020, 22(1):9. doi: 10.3390/ijms22010009.

Sex-Dependent Effects on Liver Inflammation and Gut Microbial Dysbiosis After Continuous Developmental Exposure to Trichloroethylene in Autoimmune Prone Mice.
Blossom S.J., Gokulan K., Arnold M.G., and Khare S.
Frontiers in Pharmacology. 2020, 11:569008. doi: 10.3389/fphar.2020.569008 [eCollection 2020].

Effects of Acute and Chronic Exposure to Residual Level Erythromycin on Human Intestinal Epithelium Cell Permeability and Cytotoxicity.
Hao H., Gokulan K., Piñeiro S.A., Williams K.M., Yuan Z., Cerniglia C.E., and Khare S.
Microorganisms. 2019, 7(9). pii: E325. doi: 10.3390/microorganisms7090325.

The Impact of Pristine Graphene on Intestinal Microbiota Assessed Using a Bioreactor-Rotary Cell Culture System.
Lahiani M., Gokulan K., Williams K., and Khare S.
ACS Appl Mater Interfaces. 2019, 11(29):25708-25719. doi: 10.1021/acsami.9b07635 [Epub 2019 Jul 12].

A Single or Short Time Repeated Arsenic Oral Exposure in Mice Impacts mRNA Expression for Signaling and Immunity Related Genes in the Gut.
Arnold M.G., Gokulan K., Doerge D.R., Vanlandingham M., Cerniglia C.E., and Khare S.
Food Chem Toxicol. 2019, 132:110597. doi: 10.1016/j.fct.2019.110597 [Epub 2019 Jun 21].

Alteration in the mRNA Expression of Genes Associated with Gastrointestinal Permeability and Ileal TNF-α Secretion Due to the Exposure of Silver Nanoparticles in Sprague-Dawley Rats.
Orr S.E., Gokulan K., Boudreau M., Cerniglia C.E., and Khare S.
J Nanobiotechnology. 2019, 17(1):63. doi: 10.1186/s12951-019-0499-6.

Aloin Alters the Intestinal Bacterial Community Structure and Short Chain Fatty Acids Metabolism.
Gokulan K., Kolluru P., Cerniglia C.E., and Khare S.
Front. Microbiol. 2019, doi: 10.3389/fmicb.2019.00474.

Drug Resistance in Mycobacterium tuberculosis and Targeting the L,D-Transpeptidase Enzyme.
Gokulan K. and Varughese K.I.
Drug Dev Res. 2018, doi: 10.1002/ddr.21455.

Irreversible Effects of Trichloroethylene on the Gut Microbial Community and Gut-Associated Immune Responses in Autoimmune-Prone Mice.
Khare S., Gokulan K., Williams K., Bai S., Gilbert K.M., and Blossom S.J.
J Appl Toxicol. 2019, doi: 10.1002/jat.3708.

Structure and Inhibitor Specificity of L,D-Transpeptidase (LdtMt2) from Mycobacterium Tuberculosis and Antibiotic Resistance: Calcium Binding Promotes Dimer Formation.
Gokulan K., Khare S., Cerniglia C.E., Foley S.L., and Varughese K.I.
AAPS J. 2018, 20(2):44. doi: 10.1208/s12248-018-0193-x.

Exposure to Arsenite in CD-1 Mice During Gestational to Adult Developmental Stages: Effects on Intestinal Microbiota and Gut-Associated Immune Response.
Gokulan K., Arnold M., Jensen J., Vanlandingham M., Twaddle N.C., Doerge D.R., Cerniglia C.E., and Khare S.
MBio. 2018, 9(4). pii: e01418-18. doi: 10.1128/mBio.01418-18.

An In Vitro Study to Assess the Impact of Tetracycline on the Human Intestinal Microbiome.
Jung J.Y., Ahn Y.B., Khare S., Gokulan K., Piñeiro S.A., and Cerniglia C.E.
Anaerobe. 2018, 49:85-94.

Effects of Residual Levels of Tetracycline on the Barrier Functions of Human Intestinal Epithelial Cells.
Gokulan K., Cerniglia C.E., Thomas C., Pineiro S.A., and Khare S.
Food and Chemical Toxicology. 2017, 109(1):253-263.

Graphene and Carbon Nanotubes Activate Different Cell Surface Receptors on Macrophages Before and After Deactivation of Endotoxins.
Lahiani M.H.†, Gokulan K.†, Williams K., Khodakovskaya M.V., and Khare S.
Journal of Applied Toxicology. 2017, 37(11):1305-1316.
† Contributed equally

Assessment of Antimicrobial Effects of Food Contact Materials Containing Silver on Growth of Salmonella typhimurium.
Williams K., Valencia L., Gokulan K., Trbojevich R., and Khare S.
Food and Chemical Toxicology. 2017, 100:197-206.

Lab Member

Contact information for all lab members:
(870) 543-7121
NCTRResearch@fda.hhs.gov

Kenneth J. Harris, Ph.D.
ORISE Postdoctoral Candidate