About

Jason M. Crawford is a Professor of Chemistry and of Microbial Pathogenesis at Yale University, where he has been a faculty member since 2012. He is also the Director and a member of the Institute of Biomolecular Design and Discovery. His research focuses on developing and applying genome sequence-guided methods for discovering genetically encoded small molecules from mutualistic and pathogenic microorganisms. His laboratory utilizes high-throughput genome sequencing of bacteria and fungi to identify unusual biosynthetic gene clusters suspected of synthesizing novel, structurally diverse, and biologically active small molecules. These molecules often regulate complex interactions with animal hosts, have a history of use as human drugs, and serve as molecular probes for identifying new drug targets for various diseases. His work combines small molecule chemistry, protein biochemistry, cell biology, and microbiology to explore the natural interactions between bacteria and animals, aiming to discover new signaling, antimicrobial, immunosuppressant, and anticancer molecules, connect them to their biosynthetic gene clusters, and investigate their roles in biology and medicine.

Research topics

• Biology
• Genetics
• Biochemistry
• Ecology
• Computational biology
• Microbiology
• Computer Science
• Immunology
• Stereochemistry
• Data science
• Chemistry
• Zoology
• Evolutionary biology
• Bioinformatics
• Medicine
• Pathology

Selected publications

• Natural Products as Signals across Microbiomes and the Environment

  Journal of Natural Products · 2026-03-27

  article
  PublisherDOI

• CAR-T-drug conjugate against solid tumor

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-01-02

  articleOpen access

  Chimeric antigen receptor (CAR)-T cell therapy has been clinically successful in hematologic cancers but faces challenges in solid tumors, primarily due to limited tumor infiltration, immunosuppressive tumor microenvironments (TME), and antigen heterogeneity. While combining CAR-T cell therapy with chemotherapy can enhance antitumor activity, this often leads to substantial systemic toxicity. In this study, we introduce CAR-T-drug conjugate (CAR-T-D-C), a new class of dual-functional therapeutics that effectively addresses these obstacles by integrating click chemistry for precise conjugation of cytotoxic agents onto antigen-specific CAR-T cells. By transforming the hostile TME into an ally, this approach facilitates localized delivery of cytotoxic payload directly to the tumor site, enhancing the overall effectiveness of CAR-T therapy in solid tumors. CAR-T-D-Cs with different CAR-T cell binders exhibit robust antitumor activity across diverse solid tumor models, including both human tumor xenografts and syngeneic models. Spatial transcriptomic studies reveals that CAR-T-D-C achieves improved CAR-T tumor infiltration and functional activation within the TME. Compared to conventional CAR-T therapy, CAR-T-D-C markedly enhances immune cell infiltration, augments effector functions, promotes antigen spreading, amplifies systemic immune responses, and improves overall anti-tumor immunity. CAR-T-D-C represents a versatile therapeutic concept that combines the potency of small molecule drugs and the specificity of CAR-T cells as a 2-in-1 immunochemotherapy for treatment of solid tumors.

  PublisherDOI

• A drug–microbiome–drug interaction impacts co-prescribed medications for Parkinson’s disease

  Nature Microbiology · 2026-04-06 · 1 citations

  articleOpen access

  Simultaneous prescription of multiple drugs is widespread in medicine. Although the gut microbiome is implicated in drug responses, its role in mediating drug-drug interactions is unexplored. Catechol-O-methyltransferase inhibitors (COMT-I), a class of drugs used alongside levodopa (L-DOPA) to treat Parkinson's disease symptoms, can alter microbiome composition in patients. Here we characterize the antibiotic properties of COMT-I drugs in vitro, ex vivo and in vivo and dissect how these interactions alter microbiome-mediated L-DOPA metabolism in vitro and ex vivo. Notably, in vitro iron availability determines COMT-I antibiotic activity at multiple levels: extracellular iron can drive non-enzymatic inactivation of COMT-I, rescuing COMT-I-mediated bacterial iron starvation responses. However, limitation of intracellular iron can protect sensitive bacteria from COMT-I antibiotic activity. Co-administration of COMT-I and L-DOPA to human faecal microbial communities ex vivo results in COMT-I-dependent alterations to L-DOPA metabolism in an individual-specific manner. These studies highlight a role for the gut microbiome in mediating drug-drug interactions and identify microbial features that could predict individual responses to co-prescribed drugs.

  PublisherDOI

• Three-component assembly and structure–function relationships of (–)-gukulenin A.

  ChemRxiv · 2025-07-28

  preprintOpen access

  (–)-Gukulenin A is a cytotoxic secondary metabolite that bears two aromatic α-tropolone residues, 10 asymmetric stereocenters, functionalized cyclopentane fragments, a labile hemiketal, and an electrophilic aldehyde. Here we describe an enantioselective synthesis of (–)-gukulenin A (7) by a three-component assembly strategy. Key steps include the directed C–H arylation of a norbornyl picolinamide, a tandem Grob fragmentation–alkylation, a novel method for the synthesis of α-tropolones, a site-selective, multicomponent cross-coupling reaction, and a thermal carbonyl–ene reaction to complete the carbon skeleton. (–)-Gukulenin A (7) is efficacious and well-tolerated in murine models of ovarian cancer. Structure–function studies establish the dimeric tropolone and aldehyde substructures within (–)-gukulenin A (7) as critical drivers of cytotoxicity.

  PublisherOA PDFDOI

• Discovery of a Widespread Polyamine–Low-Molecular-Weight Thiol Hybrid Pathway in <i>Clostridioides difficile</i>

  ACS Infectious Diseases · 2025-07-17

  articleOpen accessSenior authorCorresponding

  Clostridioides difficile infection can cause severe inflammation in the gastrointestinal (GI) tract, leading to diarrhea, colitis, and an increased risk of colorectal cancer. Colonization of C. difficile is associated with microbial community-level changes in the expression of polyamine and polyamine precursor biosynthesis genes. Polyamines are abundant cationic metabolites that serve indispensable functions for all kingdoms, particularly in gut homeostasis. Catabolism of the polyamine precursors arginine and ornithine offers C. difficile supplemental nutrition while subverting host immunity, yet existing models of C. difficile metabolism are incomplete regarding polyamines with comparable importance in the gut (e.g., spermidine). In this study, we conducted feeding studies with isotope-labeled polyamines and discovered a network of low-molecular-weight thiol (LMWT) molecules termed clostridithiols (CSHs) constructed from polyamines conjugated with N-acetylcysteine (NAC) moieties. NAC is clinically used as a mucolytic agent and is a well-established redox molecule. Through the analysis of a human microbiota diversity collection, we established that these previously uncharacterized hybrid metabolites are widely detected in Firmicutes and Bacteroidetes. A genetic screen using DNA from an alternative CSH producerBacteroides uniformis enabled the identification and validation of a two-gene operon, including a gene encoding a domain of unknown function, that was conserved in both producing organisms and other members of the microbiome. CSH abundance in GI mucosal biopsies positively correlated with colorectal cancer compared with matched healthy control samples. These studies indicate that human microbial metabolism broadly unites polyamine and LMWT functionalities to generate metabolites that may be associated with disease.

  PublisherOA PDFDOI

• Activity of GPCR-targeted drugs influenced by human gut microbiota metabolism

  Nature Chemistry · 2025-04-03 · 18 citations

  articleOpen accessSenior author
  PublisherOA PDFDOI

• 1102: MICROBIAL-DERIVED IMMUNOSTIMULATORY SMALL MOLECULE AUGMENTS ANTI-PD-1 THERAPY IN LUNG CANCER

  Gastroenterology · 2025-05-01

  article
  PublisherDOI

• Tryptamine Metabolism and Functionalization in Gut Commensal Bacteria Expand Human Tryptamine Signaling Responses

  ACS Chemical Biology · 2025-06-27 · 6 citations

  articleSenior authorCorresponding

  Gut microbes secrete specialized small molecules that broadly influence human physiology. Despite their potential significance, the variety of functional small molecules known in the gut is relatively limited. Here, we screened the supernatants from human fecal-derived bacterial cultures to explore their agonist effects on the human G protein-coupled receptors (GPCRs), melatonin receptor types 1A and 1B (MTNR1A, MTNR1B). Chemical analysis of the supernatant-soluble molecules of Clostridium sporogenes, a prominent gut commensal identified in the screen, led to the characterization of agonists for these two melatonin receptors. Specifically, through bioactivity-assisted isolation and characterization, we identified three small molecules, 1–3, including two previously uncharacterized metabolites, which were synthesized to confirm their structures. While the structure of 1 features a urea core symmetrically disubstituted with tryptamine moieties, 2 and 3 harbor a monomeric tryptamine functionalized with methyl carbamate and N-acetyl groups, respectively. These structural characterization efforts illuminated downstream functional consequences of tryptamine metabolism in C. sporogenes. Additional GPCR screening analyses revealed that 2 activates melatonin receptors and the purinergic P2RY11 receptor, whereas 1 serves as an agonist for the semiorphan receptor GPR55. Interestingly, 1 also exhibits significant inhibitory activity against inflammatory soluble epoxide hydrolase with a half-maximal inhibitory concentration of 420 nM. Single-cell RNA sequencing analysis of the gut tissue from mice orally treated with 1 relative to the solvent vehicle control revealed that 1 specifically decreased the frequency of GPR55- and granzyme K-expressing effector-like CD8 T cells in the intraepithelial lymphocyte population. Overall, this study broadens our understanding of tryptamine-derived signaling at the human–microbe interface.

  PublisherDOI

• The Prevalence of Microplastics in First-order Streams Across a Range of Watershed Land Uses

  Abstracts with programs - Geological Society of America · 2025-01-01

  articleSenior author
  PublisherDOI

• Three-component assembly and structure–function relationships of (–)-gukulenin A.

  ChemRxiv · 2025-07-29

  preprint

  (–)-Gukulenin A is a cytotoxic secondary metabolite that bears two aromatic α-tropolone residues, 10 asymmetric stereocenters, functionalized cyclopentane fragments, a labile hemiketal, and an electrophilic aldehyde. Here we describe an enantioselective synthesis of (–)-gukulenin A (7) by a three-component assembly strategy. Key steps include the directed C–H arylation of a norbornyl picolinamide, a tandem Grob fragmentation–alkylation, a novel method for the synthesis of α-tropolones, a site-selective, multicomponent cross-coupling reaction, and a thermal carbonyl–ene reaction to complete the carbon skeleton. (–)-Gukulenin A (7) is efficacious and well-tolerated in murine models of ovarian cancer. Structure–function studies establish the dimeric tropolone and aldehyde substructures within (–)-gukulenin A (7) as critical drivers of cytotoxicity.

  PublisherDOI

Recent grants

• Ecological triggers to exploit antibiotic and virulence factor regulation

  NIH · $721k · 2011–2015

• Structural and functional studies of colibactin

  NIH · $5.5M · 2017–2028

• Predoctoral Training at the Interface Chemistry and Biology

  NIH · $6.6M · 2003–2023

• Ecological triggers and transcriptional profiling to guide antibiotic discovery

  NIH · $90k · 2011–2012

• Cryptic gut bacterial metabolites that regulate colorectal cancer formation

  NIH · $2.5M · 2013–2018

Frequent coauthors

• Hyun Bong Park

  29 shared

• Joonseok Oh

  Yale University

  23 shared

• Seth B. Herzon

  University of New Haven

  20 shared

• Jo Handelsman

  University of Wisconsin–Madison

  20 shared

• Richard A. Flavell

  Howard Hughes Medical Institute

  19 shared

• Juan I. Bravo

  University of Southern California

  18 shared

• Gabriel L. Lozano

  Wisconsin Institutes for Discovery

  18 shared

• Craig A. Townsend

  Johns Hopkins University

  17 shared

Awards & honors

• Sarah and Adolph Roseman Achievement Award (2007)
• Damon Runyon Cancer Research Foundation Postdoctoral Fellows…
• National Institutes of Health Pathway to Independence Award,…
• Damon Runyon Cancer Research Foundation Dale F. Frey Award f…
• Searle Scholars Award (2013)