April, 2021. Congrats Alex on your review being accepted in Nature Chem Bio. This review synthesizes the latest advancements on E. coli small molecule metabolism at the host-microbe interface.
March, 2021. Congrats Rachelle for being awarded a 2021 NSF Graduate Research Fellowship. This award places Rachelle among an “elite group of fellows,” many of which who have gone on to distinguished careers in STEM.
November, 2020. See Tayah’s Preview at Cell Chem Bio on the dual targeting of v-ATPase and mTORC1 signaling in multidrug-resistant cancers.
October, 2020. Congrats Emilee on your review being accepted at the Annual Review of Biochemistry. This review synthesizes the latest advancements on Molecules from the Microbiome.
June, 2020. Congrats Louis, Joonseok, Sabine, and Nam on your research article being accepted at Angew. Chem. Int. Ed. This paper identified the biosynthetic pathway and genetic distribution of the famous protease inhibitor known as leupeptin. A new class of proteases was discovered that was responsible for regulating a proteolytic divergence point between the peptide aldehyde protease inhibitors and “propyrazinones” featuring a novel hetero-tricyclic architecture. Under aerobic conditions, the propyrazinones transform into pyrazinones. The study also found that the leupeptin pathway was enriched in clinical Klebsiella pathogens associated with respiratory tract pathologies, whereas the Klebsiella tilimycin/tilivalline enterotoxin pathway was associated with intestinal tract pathologies.
June, 2020. Congrats Hyun Bong, Zheng, and team on your research article being accepted at Nature Micro. Antibiotics are widely used to treat infectious diseases, but some of these drugs have immunological activities in the host itself. How these immunological phenotypes are regulated at the molecular level remain largely undefined. In this study, a new model is presented, in which sub-growth inhibitory levels of antibiotics that do not deleteriously affect intestinal colonization can indirectly regulate immune system function through the activation of novel bacterial stress responses. A new stress response pathway, the “colipterins,” in E. coli is characterized at the detailed structural, functional, and genetic levels in cell culture and in vivo.
May, 2020. Congrats Kevin and crew on your review being accepted in Bioorg. Med. Chem. Lett. This review focuses on the structure and activity of colibactin and some current directions that are now possible due to synthetic access of the molecules.
May, 2020. Congrats Tyler, Jaymin, and Hyun Bong on your research communication being accepted in Biochemistry. This work describes the mode of action of dimeric stilbene antibiotics that are active against drug-resistant Gram-positive pathogens, including MRSA and VRE. Importantly, the lead antibiotic did not lead to substantial resistance in MRSA even after daily sub-lethal treatments for a period of 3 months.
May, 2020. Congrats Jasmina on your article being accepted in Science Advances. This study used high-resolution in situ Raman microspectroscopy to capture physiological signals preserved in deep time and reconstruct phylogenetic information in dinosaur fossil biomolecules.
May, 2020. Congrats Nneoma, Hyun Bong, and team on your recent article being accepted in J. Nat. Prod. This work identifies a novel DNA repair inhibitor that exhibits synthetic lethality in PTEN-deficient glioblastoma. Interestingly, the molecule appears to be derived from a Maillard-like biosynthetic pathway.
April, 2020. Congrats Jason on receiving tenure. Jason sincerely thanks all of his former and current lab members for making this possible. He also sincerely thanks his collaborators and mentoring committee for important insights along the way.
April, 2020. We welcome Rachelle Hunt to the lab as a Microbiology graduate student from Northeastern University.
March, 2020. Congrats Tayah for being awarded a 2020 NSF Graduate Research Fellowship. This award places Tayah among an “elite group of fellows,” many of which who have gone on to distinguished careers in STEM.
March, 2020. Congrats Randy for being awarded a 2020 Ford Foundation Predoctoral Fellowship. The Ford Foundation supports academic diversity and recognizes exceptional graduate students who demonstrate superior academic achievement, are committed to a career in university teaching, research, and education, and are prepared to use diversity as a resource for enriching the educational experience for all students.
March, 2020. Congrats Tyler for defending your thesis. Good luck with your new position in Boston.
March, 2020. Congrats Chung Sub, Louis, and team on your indole-functionalized metabolite signaling work in E. coli being accepted as a research article at Cell Chem Bio. This paper identifies a new metabolic stress response in E. coli that produces molecules that increase persister cell formation, an antibiotic tolerant state. Some of the molecules were previously described as byproducts of the plant innate immune system; however, they were produced in a convergent evolutionary manner in E. coli relative to plants. Additionally, the molecules regulated the aryl-hydrocarbon receptor (AhR) patwhay and interleukin-6 signaling in human tissues. Thus, the molecules appear to regulate stress responses in bacteria, plants, and humans.
February, 2020. Congrats Hyun Bong, Tyler, and team on your autoimmune drug metabolism work being accepted as a “Hot Paper” and VIP research article in Angew Chem Int Ed. In our past work, we showed that an antibiotic could be biotransformed by gut microbiota members into an immunomodulator (JOC, 2018), and in the current work, we demonstrated that a stilbene immunomodulator could be biotransformed into an antibiotic. While the structural transformations eliminated immunomodulatory drug efficacy in a colitis mouse model, they endowed the products with new antimicrobial functionalities against multi-drug resistant bacterial pathogens. A bacterial cupin enzyme enhanced dimerization of stilbene precursors, and their dimeric products underwent a complex carbocyclization reaction leading to a conjugated cyclopropane-containing metabolite with a hexacyclic framework. Because stilbenes are common in our diet, the study also raises new questions regarding the functions of stilbenes at the diet-microbe-host interface.
January, 2020. Congrats to Emilee Shine and Chung Sub Kim for securing postdoctoral and faculty positions, respectively. Emilee defended her thesis in Microbiology and will be joining the Bonnie Bassler lab at Princeton. Chung Sub will be starting an Assistant Professor position at the School of Pharmacy, Sungkyunkwan University, in South Korea. Great news all around!
January, 2020. Congrats Chung Sub, Alex, Santiago, and team on the characterization of the structure and biosynthesis of autoinducer-3 in E. coli, which was reported in ACS Central Science. This work provides molecular resolution to a nearly 20-year challenge in the bacterial pathogenesis field. Remarkably, the molecules are produced in a variety of human pathogens and regulate bacterial virulence and host immune responses. These molecular studies now open the door for diverse biological studies of these elusive, yet widely distributed bacterial signaling molecules.
September, 2019. Congrats Joonseok, Nam, and Haiwei on your recent article being accepted in JACS. This article describes a family of novel “opine-glycopeptides” that are derived from an “Ugi-like” biosynthetic pathway in pathogenic Xenorhabdus and Photorhabdus species. The new molecules were produced at about 25 micromolar in cell culture and activated the human G-protein coupled receptor (GPCR) bombesin receptor-subtype-3 at 1 micromolar and higher, supporting a physiologically-relevant response.
August, 2019. Congrats Alan, Kevin, Chung Sub, and Nicholas on your research article being accepted in Nature Chemistry. This paper describes the unexpected degradation routes of precolibactins. Unprecedented reactivity of an alpha-aminoketone precursor, spontaneous oxidation, hydrolysis, and nucleophilic fragmentation, explained the instablity of (pre)colibactins. Additionally, through an understanding of this new reactivity, we were able to rationally propose and chemically support the structures of (pre)colibactin in the associated research article in Science.
July, 2019. Congrats Lucy, Chung Sub, and team on your colibactin structure elucidation paper being accepted in Science. In this study, the structure of colibactin and its DNA interstrand crosslink products were unambigously defined. This work was the result of a wonderful collaboration with the Herzon group. Strong support for the structure, reactivity, instability, and biosynthesis of colibactin only came from a seamless combination of synthetic, biosynthetic, metabolomic, genetic, and DNA alkylation studies. Unexpected serine isotope labeling results, which were not predictable from bioinformatics analysis, contributed to the structural proposal. This study also nicely built on our team’s prior study where the chemical degradation routes of precolibactins were defined revealing the unexpected and nonobvious chemical reactivity of an alpha-aminoketone precursor – spontaneous oxidation, hydrolysis, and nucleophilic fragmentation. See the associated news articles: Chemical & Engineering News, Yale News, and Nature Chem Bio.
July, 2019. Congrats Nam Kim and Yick Chong Lam on defending your theses and securing research and consulting jobs, respectively.
July, 2019. Congrats “biolum team” on your research article in iScience describing the molecular foundations of bright-green biofluorescence broadly distributed in marine animals, including sharks. Just in time for shark week at the end of July. See the associated news articles: CNN, New York Times, National Geographic, PBS, Science, Science Daily, News Week, Cosmos Magazine, Earth, Ars Technica, Inside Science, The Gaurdian, ABC News, New Scientist, Science Alert, Chemistry & Engineering News, Yahoo Finance, BBC News, Forbes, Chemistry World, and many others.
April, 2019. Congrats Nam, Tyler, and Seungjung on your recent article being published in ChemBioChem. This study identifies the first lead biocatalysts capable of reversing a mature advanced glycation end product (AGE) in a peptide context. Such catalysts could be further evolved and developed to generate new molecular tools to study the biology of AGEs.
April, 2019. We welcome Randy Hamchand, Nata Dudkina, and Tayah Turocy to the lab as Chemical Biology graduate students from the University of Connecticut, the University of Vermont, and Youngstown Sate University, respectively.
April, 2019. Congrats Haiwei, Phu-Khat, and crew on your recent article being published in Cell. This exciting paper exploits the microbiome to discover molecules that regulate both known and orphan G-protein coupled receptors (GPCRs). The studies illuminated various diet-microbe-host and microbe-microbe-host metabolic axes that regulated both local and systemic host physiological responses.
April, 2019. See Zheng’s Biochemistry Viewpoint on the potential functional roles of gut microbe-produced nitric oxide.
March, 2019. Congrats Gabriel, Hyun Bong, Juan, and crew on your research article being published at AEM. This paper describes a family of new tetrahydropyridine alkaloids broadly distributed in Pseudomonas species. Bacteria in the rhizosphere produced “plant-type” metabolites through a convergent evolutionary route that regulated interbacterial competition in the rhizosphere microbiome.
January, 2019. Congrats Corey on your research article being acceted at Biochemistry. This paper describes a new group of metabolites, “glycoaminoacids,” which are produced in a different way than established glycopeptides. Rather than glycosylation, in which a peptide is functionalized with a sugar, here, an oligosaccharide is functionalized with an aminoacid. The new glycoaminoacid termed “photolose” is a glycylated-disaccharide featuring a 1,6-anhydro-β-d-N-acetyl-glucosamine moiety. The molecule is produced by an atypical carbohydrate-nonribosomal peptide synthetase-type hybrid system, in which a hypothetical protein serves as a bridge between these two biosynthetic systems. We further demonstrate that the gene cluster confers a bacterial growth advantage to antimicrobial peptide challenge.
January, 2019. Congrats Gabriel and crew on your paper recently being accepted at mBio. This paper describes a model microbiome system for genetic dissection of community behavior.
October, 2018. Congrats Lucy and Emilee on your recent colibactin Communication in Biochemistry. This paper provides the first direct evidence of natural colibactin-nucleobase adducts and supports our mechanistic model for colibactin genotoxicity, in which the DNA is alkylated through colibactin cyclopropane ring opening.
October, 2018. See Scientia’s commentary of our work.
September, 2018. See Emilee’s and Lucy’s co-first author publication demonstrating that model colibactins exhibit cellular genotoxicity in the absence of host bacteria. This experimentally-rich paper defines key biosynthetic domains that convert potent DNA alkylators into potent DNA interstrand crosslinkers. They also show that module-skipped natural colibactins exhibit shared phenotypes in vitro with closely related synthetic metabolites. Lastly, they provide evidence that colibactins can be intercepted by extracellularly-supplemented ClbS and that membranes may limit the diffusion of colibactins, which may account for its cell-to-cell contact phenotype. This work was published in ACS Chem Bio.
April, 2018. We welcome Zheng Wei to the lab as a joint graduate student with Richard Flavell in Immunobiology. Zheng joins us from Peking University.
April, 2018. Congrats Corey on defending your thesis.
April, 2018. Congrats Joonseok, Jaymin, and Hyun Bong on your work being published in J. Org. Chem as part of their Special Issue on Antibiotics. In contrast to most drug metabolism studies that show drug catabolism and inactivation, this study demonstrates how the antibiotic amoxicillin can be biotransformed by gut microbiota members into an immunostimulant that lacks antibacterial properties – a functional transformation process. Amoxicillin was previously shown to have minimal long-term impacts on human microbiota composition in clinical trial studies. Taken together, the study supports a new model for how antibiotics could indirectly regulate immune function in a stable, microbiome-dependent manner.
March, 2018. See Yick’s Nature Micro News & Views on discovering antibiotics from the global microbiome.
January, 2018. Congrats Jason on receiving the Maxine F. Singer ‘57 Chair. Jason is now the Maxine F. Singer ‘57 Ph.D. Associate Professor of Chemistry and Microbial Pathogenesis. See the YaleNews article.
January, 2018. See Jaymin’s Biochemistry Viewpoint on the microbiota contributions to cancer immunotherapy outcomes.
November, 2017. See the YaleNews article about our collaborative research on the elucidation of luciferin biosynthesis.
November, 2017. Congrats Prabhanshu, Emilee, Alan, and Chung Sub on your recent JACS communication, leading to the discovery of a novel enzyme – a cyclopropane hydrolase – that confers resistance to colibactin. Structure-function studies are described for the new enzyme and its biochemical reaction. Colibactin has been linked to colorectal cancer pathogenesis, and the mechanistic insights gained from these studies not only support a resistance mechanism at the molecular level, but also significantly expand our knowledge on colibactin’s mode of action.
November, 2017. Congrats Corey and Hyun Bong on your Biochemistry article, biochemically characterizing the first pteridine-nonribosomal peptide hybrid pathway from the entomopathogen Photorhabdus luminescens. The paper provides important insights for the novel pathway’s biological functions at the protein, metabolic, and cellular levels. Interestingly, the bacterial cellular redox pathway appears to regulate pathways associated with quorum sensing, antibiosis, and nematode host development.
September, 2017. See Eric’s Biochemistry Viewpoint on a novel nucleoside antibiotic that targets bacterial RNA polymerase. Yet again, natural products come to the rescue for identifying novel drug binding sites and modes of action for targeting pathogenic bacteria.
August, 2017. Congrats Sandhya and Alan on your ACS Chem Bio article defining the structure and function of an unusual intermediate-releasing thioesterase (TE) at the molecular level from the colibactin biosynthetic pathway. This paper provides new insights into the post-translational regulatory aspects of a bacterial genotoxic pathway in the gut linked to colorectal cancer formation. The enzyme was shown at the biochemical level to regulate the release of critical intermediates required for genotoxicity while removing aberrant enzyme products that shut down the enzymatic system.
July, 2017. Congrats to Eric Trautman for successfully defending his PhD thesis. Good luck with your next steps in consulting.
July, 2017. We welcome Alexandra (Alex) Gatsios to the lab as a Chemical Biology graduate student from Smith College.
May, 2017. Congrats Jason for receiving a Burroughs Wellcome Investigators in the Pathogenesis of Infectious Disease (PATH) Award. Our PATH project focuses on defining cell-to-cell stress communications in pathogenic bacteria and in human-bacteria interactions. Jason would like to thank Jaymin Patel for bringing a 30-thousand foot vision on paper to nearing practical solutions at the bench. Jason would also like to thank Chung Sub Kim, Hyun Bong Park, and Corey Perez on their associated bacterial cell-to-cell stress communication work. See the associated YaleNews article.
May, 2017. Congrats Jason for receiving the Camille Dreyfus Teacher-Scholar Award.
April, 2017. Congrats Jason for being named as a William Raveis Charitable Fund scientist through the Damon Runyon Cancer Research Foundation. The William Raveis Charitable Fund in partnership with the Damon Runyon Foundation has planned a series of events across the Northeast to raise awareness about the importance of more broadly supporting cancer research.
February, 2017. Congrats Hyun Bong, Corey, and Karl on your paper being accepted to eLife. This study identifies the first example of a hybrid nonribosomal peptide synthetase-like-pteridine synthase biosynthetic gene cluster. The paper describes synteny-based genome mining, genetics, pathway-targeted metabolomics, and quantitative proteomics analyses that led to the new metabolite structures encoded by the unprecedented pathway, the “pepteridines,” in Photorhabdus luminescens. The pepteridines are produced only in a phenotypic variant associated with bacterial pathogenesis and not in the variant associated with mutualistic colonization. Genetics and proteomics further supported that the pathway was under the control of a LysR-type regulator associated with the mutualist-pathogen transition and affected the regulation of proteins that govern pyrone quorum sensing and other defensive genetic loci. See also Yale West Campus News.
February, 2017. Congrats Hyun Bong, Parthasarathy, Corey, Joon Ha, and Jeannie on your paper being accepted to J. Biol. Chem. This was a multi-group collaboration with Steven Almo, Elissa Hallem, and Jeffrey Bonanno. The paper describes the X-ray structure and biochemical characterization of an orphan FAD-dependent monooxygenase that catalyzes the stereoselective epoxidation of stilbenes in Photorhabdus luminescens. Stilbenes participate in antibiosis, immunomodulation, and nematode developmental biology in this system. The newly described (bio)chemistry was examined in two distinct animal models. The data support a stilbene detoxification route in the bacteria-nematode symbiosis.
February, 2017. Congrats Eric, Alan, and Emilee on your domain-targeted metabolomics paper being accepted to JACS. This paper combines multiplex automated genome engineering with pathway-targeted analyses to delineate the heterocycle assembly steps of colibactin biosynthesis. In addition to illuminating unexpected catalytic timing events in colibactin biosynthesis, the study also unveiled and structurally confirmed new reactive precolibactins. Upon peptidase treatment, these reactive metabolites were converted to a genotoxic scaffold consistent with the pathway’s genotoxic role associated with colorectal cancer. The domain-targeted metabolomics approach is general and could be widely applied to “multidomain” pathways for unprecedented genetic and metabolic precision analyses. See also the JACS Spotlight.
January, 2017. Congrats Thomas, Stephanie, and Christina on your paper being accepted to ChemBioChem. This paper describes an “orphan” gene cluster in Legionella pneumophila, the causative agent of Legionnaires’ disease. The single gene cluster produces two distinct groups of aromatic amino acid-derived metabolites, including new N-acyl-amide and known isocyanide metabolites. One of the new N-acyl-amides harbored a cyclopropane moiety derived from cyclopropane fatty acid synthase. The paper also develops a general tetrazine-based chemoselective ligation approach to identify isocyanide-functionalized metabolites.
December, 2016. Congrats Caleb on your paper being accepted to eLife. This paper shows how intermicrobial chemical exchange in the microbiome can regulate animal behaviors. Such interactions are missed in the more common single microbe metabolic studies.
November, 2016. Congrats Alan, Herman, and Jaymin on your colibactin paper being accepted to JACS. This paper provides a robust mechanistic model for colibactin genotoxic reactivities and unifies the currently observed small molecule chemistry of the colibactin pathway.
June, 2016. Congrats Hyun Bong, Corey, and Elena on your amicoumacin paper being accepted to Molecules. This paper illuminates a new amicoumacin antibiotic resistance mechanism and also provides the first mode of action insights for N-acyl-D-Asn pro-drug motifs in nonribosomal peptide-polyketide hybrid metabolites.
June, 2016. Congrats Hyun Bong on your pyrazinone paper being accepted to J. Antibiot. This paper demonstrates that novel pyrazinones in Photorhabdus pathogens are only produced in a phenotypic variant associated with pathogenesis and provides new insights for how this class of protease inhibitors may participate in host-bacteria interactions.
May, 2016. We welcome Tyler Goddard to the lab as a Chemical Biology graduate student from Baylor University.
May, 2016. We welcome Phu Khat Nwe to the lab as a Chemical Biology graduate student from Albion College.
May, 2016. We welcome Jhe-Hao Li to the lab as a Chemical Biology graduate student from the National Taiwan University.
April, 2016. We welcome Chung Sub Kim to the lab as a postdoctoral associate from the Kang Ro Lee lab at the Sungkyunkwan University.
March, 2016. Congratulations Emilee Shine on receiving a NSF Graduate Research Fellowship.
March, 2016. Congratulations Alan and Maria on your precolibactin synthesis paper being published in JACS. This paper demonstrates that the colibactin warhead undergoes a cyclization cascade, assembling from acyclic precursors, and that the colibactin peptidase can process advanced precolibactin C into N-myristoyl-D-Asn and colibactin C.
February, 2016. We welcome Christina Cho to the lab as a Chemistry graduate student from Macaulay Honors College at Queens College. We also welcome Helen Zhao as an undergraduate researcher in the lab.
January, 2016. Congratulations Jason for receiving a Damon Runyon-Rachleff Innovation Award. Go “M-PAIR” cancer team!
October, 2015. We welcome Joonseok Oh to the lab as a postdoctoral associate from the Hamann lab at the University of Mississippi.