Microbial small molecules associated with host microbiome
Eukaryotes, including humans and marine organisms, are 'petri dishes', hosting an abundant and a rich prokaryotic 'microbiome'. The Garg Lab aims to understand the molecular interactions between a eukaryotic host and its microbiome, and how these molecular interactions affect health and disease status.
The overarching goal of Dr. Garg’s research is to learn how pathogens and beneficial bacteria affect metabolism and function of a host, then turning that around to learn how to develop microbiome-based and microbiome-targeted therapies. Antibiotics aren’t effective against majority of the airway infections in the current scenario, and we desperately need innovative and alternative biochemical pathways that can be targeted to finetune potency and efficacy of existing drugs. Garg lab develops chemistry-first approaches to identify microorganisms, biochemical pathways and specialized metabolites also called natural products towards this goal that can be engineered to prevent pathogens from colonizing the airways and causing an infection. Furthermore, Garg lab believes understanding how pathogens and the host microbiome interact with drugs and specialized metabolism is important to develop holistic understanding of treatment outcomes. To gain comprehensive understanding of chemical crosstalk between drugs, the microbiome, and the host, Garg lab applies interdisciplinary approaches in chemical microbiology, genetics, microscopy, metabolomics, mass spectrometry imaging, (meta) transcriptomics and genomics to unveil biochemical mechanisms of chemical crosstalk. Her work promises to shape our understanding of metabolism, cell biology, physiology, and microbial function by application of a multitude of model systems including mammalian cell culture, synthetic microbiomes, and animal models.
The overarching goal of Dr. Garg’s research is to learn how pathogens and beneficial bacteria affect metabolism and function of a host, then turning that around to learn how to develop microbiome-based and microbiome-targeted therapies. Antibiotics aren’t effective against majority of the airway infections in the current scenario, and we desperately need innovative and alternative biochemical pathways that can be targeted to finetune potency and efficacy of existing drugs. Garg lab develops chemistry-first approaches to identify microorganisms, biochemical pathways and specialized metabolites also called natural products towards this goal that can be engineered to prevent pathogens from colonizing the airways and causing an infection. Furthermore, Garg lab believes understanding how pathogens and the host microbiome interact with drugs and specialized metabolism is important to develop holistic understanding of treatment outcomes. To gain comprehensive understanding of chemical crosstalk between drugs, the microbiome, and the host, Garg lab applies interdisciplinary approaches in chemical microbiology, genetics, microscopy, metabolomics, mass spectrometry imaging, (meta) transcriptomics and genomics to unveil biochemical mechanisms of chemical crosstalk. Her work promises to shape our understanding of metabolism, cell biology, physiology, and microbial function by application of a multitude of model systems including mammalian cell culture, synthetic microbiomes, and animal models.
Atharva et al, Natural Products Reports, 2025
Biological and Chemical Interactions Spanning Different Scales
The Garg laboratory investigates natural product mediated chemical interactions at several scales
1. Phenotypic scale: Effect of microbial phenotypes such as quorum sensing and pigmentation on natural product chemical space of individual microbes
1. Phenotypic scale: Effect of microbial phenotypes such as quorum sensing and pigmentation on natural product chemical space of individual microbes
2. Microbe-Environment: Presence of antimicrobials and changes in nutrients
3. Microbe-Microbe
4. Bacterial-fungal interactions
5. Microbe-host cell (mammalian cell metabolomics): Bacterial pathogen during infection of its host
5. Whole organism/holobiont
Tools used in our lab
The Garg laboratory uses a wide array of contemporary techniques in mass spectrometry complemented by (meta)genomics, microbiology, and biochemistry.
Mass spectrometry based three dimensional spatial mapping
We reconstruct 3-D models of human organs from CT scans and MRI images. We then overlay the spatial abundances of microbes (which we determine by DNA sequencing) and small molecules (which we find by mass spectrometry) on the human organ 3-D models to visualize correlations between the microbiome and the metabolome. These correlations allow us to determine (i) how the microbiome and the host are talking with each other at the molecular level using small molecules; (ii) whether the host is generating an immune response specific to the microbiome; (iii) whether clinically administered antibiotics and drugs affect the microbiome and the host; and (iv) how the microbiome-host community is structured. Our findings have broad implications on human health and disease and training opportunities exist for postdocs, graduate students, undergraduates, and research scientists interested in mass spectrometry, microbiology, and biochemistry.
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3D organ mapping
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Distribution of various antibiotics administered to the patients in the cystic fibrosis associated explant human lung. |
Distribution of the microbe Pseudomonas aeruginosa (left), Staphylococcus aureus (middle), and small molecule virulence factors produced by P. aeruginosa (right) in the cystic fibrosis associated human explanted lungs.
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Mass spectrometry based molecular networking
The volume of information in a single mass spectrometry experiment can easily overwhelm manual curation and inventory. Then, how do we tackle a problem in which thousands of mass spectrometry experiments have to be conducted for a single dataset to tackle problems in human health and disease? The Garg lab uses techniques in molecular networking to visualize and organize large volumes of mass spectrometry data to derive meaningful correlations between metadata (conditions from which analytical samples were derived from) and the small molecule metabolome. These correlations are then tested and validated in the lab using a diversity of techniques in microbiology, molecular biology, and biochemistry. We also collaborate with clinicians to directly advance our findings to a clinical setting.
Patient specific detection of Pseudomonas aeruginosa small molecules
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Disease specific drug metabolism: enables development of improved drugs.
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Mass spectrometry imaging of polymicrobial communities
We use various wet lab techniques to mimic and understand molecular interactions in microbial communities. This allows us to test relevant hypotheses that are generated from direct analyses of human tissue using the abovementioned tools of spatial mapping and molecular networking. One of the tools that we use employs direct visualization of microbes interacting in a petri dish using mass spectrometry based microbial imaging. The Garg lab has access to cutting-edge mass spectrometers that allow high resolution imaging experiments to be performed with minimal sample manipulations. Our experiments are directed towards to questions that are directly relevant to human health, as well as complex community structures in the environment.
Stenotrophomonas specific small molecules produced only during interaction with Pseudomonas aeruginosa.
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Multimodal imaging of marine corals
Genetic and biochemical bases for small molecule production
The microbial molecules that we find in complex communities using mass spectrometry are naturally produced using a set of dedicated genes encoded within the genomes of participating bacteria. We find these sets of genes, often organized in genetic neighborhoods called 'biosynthetic gene clusters', and use techniques in molecular biology, microbiology, and biochemistry to connect the genotype to the chemotype, and eventually to the phenotype in the community structure. We employ techniques involving expression of genes in different microbial hosts and biochemical characterization of biosynthetic enzymes.
