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APIR:Aggregating Universal proteomics Database Search Algorithms for Peptide Identification with FDR Control

Genomics, proteomics & bioinformatics 2024年第2期22卷 171-187页

作者： Yiling Elaine Chen Xinzhou Ge Kyla Woyshner MeiLu McDermott Antigoni Manousopoulou Scott B.Ficarro Jarrod A.Marto Kexin Li Leo David Wang Jingyi Jessica Li Department of Statistics and Data Science University of CaliforniaLos AngelesCA 90095USA Department of Immuno-Oncology Beckman Research InstituteCity of Hope National Medical CenterDuarteCA 91010USA Department of Quantitative and Computational Biology University of Southern CaliforniaLos AngelesCA 90089USA Department of Cancer Biology and Blais Proteomics Center Dana-Farber Cancer InstituteDepartment of PathologyBrigham and Women’s Hospital and Harvard Medical SchoolBostonMA 02215USA Department of Pediatrics City of Hope National Medical CenterDuarteCA 91010USA Bioinformatics Interdepartmental Program University of CaliforniaLos AngelesCA 90095USA Department of Human Genetics University of CaliforniaLos AngelesCA 90095USA Department of Computational Medicine University of CaliforniaLos AngelesCA 90095USA Department of Biostatistics University of CaliforniaLos AngelesCA 90095USA

Advances in mass spectrometry(MS)have enabled high-throughput analysis of proteomes in biological *** state-of-the-art MS data analysis relies on database search algorithms to quantify proteins by identifying peptide–spectrum matches(PSMs),which convert mass spectra to peptide *** database search algorithms use distinct search strategies and thus may identify unique ***,no existing approaches can aggregate all user-specified database search algorithms with a guaranteed increase in the number of identified peptides and a control on the false discovery rate(FDR).To fill in this gap,we proposed a statistical framework,Aggregation of Peptide Identification Results(APIR),that is universally compatible with all database search ***,under an FDR threshold,APIR is guaranteed to identify at least as many,if not more,peptides as individual database search algorithms *** of APIR on a complex proteomics standard dataset showed that APIR outpowers individual database search algorithms and empirically controls the *** data studies showed that APIR can identify disease-related proteins and post-translational modifications missed by some individual database search *** APIR framework is easily extendable to aggregating discoveries made by multiple algorithms in other high-throughput biomedical data analysis,e.g.,differential gene expression analysis on RNA sequencing *** APIR R package is available at https://***/yiling0210/APIR.

关键词： Shotgun proteomics Peptide–spectrum match Peptide identification Aggregation of lists FDR control

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Dual-targeting compounds possessing enhanced anticancer activity via microtubule disruption and histone deacetylase inhibition

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European Journal of Medicinal Chemistry 2024年 265卷 116042页

作者： Tseng, Yu-Wei Yang, Tsung-Jung Hsu, Yuan-Ling Liu, Jyung-Hurng Tseng, Yin-Chen Hsu, Tse-Wei Lu, Yueh Pan, Szu-Hua Cheng, Ting-Jen Rachel Fang, Jim-Min Department of Chemistry National Taiwan University Taipei 106 Taiwan Graduate Institute of Medical Genomics and Proteomics College of Medicine National Taiwan University Taipei 100 Taiwan Graduate Institute of Genomics and Bioinformatics College of Life Sciences National Chung Hsing University Taichung 40227 Taiwan The Genomics Research Center Academia Sinica Taipei 115 Taiwan Doctoral Degree Program of Translational Medicine National Taiwan University Taipei 100 Taiwan Genome and Systems Biology Degree Program National Taiwan University and Academia Sinica Taipei 100 Taiwan

Dual-targeting anticancer agents 4–29 are designed by combining the structural features of purine-type microtubule-disrupting compounds and HDAC inhibitors. A library of the conjugate compounds connected by appropriate linkers was synthesized and found to possess HDACs inhibitory activity and render microtubule fragmentation by activating katanin, a microtubule-severing protein. Among various zinc-binding groups, hydroxamic acid shows the highest inhibitory activity of Class I HDACs, which was also reconfirmed by three-dimensional quantitative structure-activity relationship (3D-QSAR) pharmacophore prediction. The purine–hydroxamate conjugates exhibit enhanced cytotoxicity against MDA-MB231 breast cancer cells, H1975 lung cancer cells, and various clinical isolated non-small-cell lung cancer cells with different epidermal growth factor receptor (EGFR) status. Pyridyl substituents could be used to replace the C2 and N9 phenyl moieties in the purine-type scaffold, which can help to improve the solubility under physiological conditions, thus increasing cytotoxicity. In mice treated with the purine–hydroxamate conjugates, the tumor growth rate was significantly reduced without causing toxic effects. Our study demonstrates the potential of the dual-targeting purine–hydroxamate compounds for cancer monotherapy. © 2023 Elsevier Masson SAS

关键词： Breast cancer Histidine deacetylase Hydroxamate Katanin Lung cancer Microtubule Purine-type conjugate

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RETRACTION: IspH inhibitors kill Gram-negative bacteria and mobilize immune clearance (Retraction of Vol 589, Pg 597, 2021)

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NATURE 2021年第7885期599卷 518-518页

作者： Singh, Kumar Sachin Sharma, Rishabh Reddy, Poli Adi Narayana Vonteddu, Prashanthi Good, Madeline Sundarrajan, Anjana Choi, Hyeree Muthumani, Kar Kossenkov, Andrew Goldman, Aaron R. Tang, Hsin-Yao Totrov, Maxim Cassel, Joel Murphy, Maureen E. Somasundaram, Rajasekharan Herlyn, Meenhard Salvino, Joseph M. Dotiwala, Farokh Vaccine and Immunotherapy Center The Wistar Institute Philadelphia PA USA Program in Molecular and Cellular Oncogenesis The Wistar Institute Philadelphia PA USA Molecular Screening and Protein Expression Facility The Wistar Institute Philadelphia PA USA Bioinformatics Facility The Wistar Institute Philadelphia PA USA Proteomics and Metabolomics Facility The Wistar Institute Philadelphia PA USA Molsoft San Diego CA USA

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Sorbate induces lysine sorbylation through noncanonical activities of class I HDACs to regulate the expression of inflammation genes

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Science advances 2025年第22期11卷 eadv1071页

作者： Yi-Cheng Sin Breann Abernathy Zuo-Fei Yuan Jason L Heier Justin E Gonzalez Laurie L Parker Douglas G Mashek Yue Chen Department of Biochemistry Molecular Biology and Biophysics University of Minnesota Twin Cities Minneapolis MN USA. Bioinformatics and Computational Biology Program University of Minnesota Twin Cities Minneapolis MN USA. Center for Proteomics and Metabolomics St. Jude Children's Research Hospital Memphis TN USA. Department of Medicine Division of Diabetes Endocrinology and Metabolism University of Minnesota Twin Cities Minneapolis MN USA. Institute for the Biology of Aging and Metabolism University of Minnesota Twin Cities Minneapolis MN USA.

Environmental factors may affect gene expression through epigenetic modifications of histones and transcription factors. Here, we report that cellular uptake of sorbate, a common food preservative, induces lysine sorbylation (Ksor) in mammalian cells and tissue mediated by the noncanonical activities of class I histone deacetylases (HDAC1-3). We demonstrated that HDAC1-3 catalyze sorbylation upon sorbate uptake and desorbylation in the absence of sorbate both in vitro and in cells. Sorbate uptake in mice livers significantly induced histone Ksor, correlating with decreased expressions of inflammation-response genes. Accordingly, sorbate treatment in macrophage RAW264.7 cells upon lipopolysaccharide (LPS) stimulation dose-dependently down-regulated proinflammatory gene expressions and nitric oxide production. Proteomic profiling identified RelA, a component of the NF-κB complex, and its interacting proteins as bona fide Ksor targets and sorbate treatment significantly decreased NF-κB transcriptional activities in response to LPS stimulation in RAW264.7 cells. Together, our study demonstrated a noncanonical mechanism of sorbate uptake in regulating epigenetic histone modifications and inflammatory gene expression.

关键词： Transcription

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Adverse Health Correlates of Intimate Partner Violence against Older Women: Mining Electronic Health Records

arXiv

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arXiv 2022年

作者： Yılmaz, Serhan Günay, Erkan Lee, Da Hee Whiting, Kathleen Silver, Kristen Koyutürk, Mehmet Karakurt, Günnur Case Western Reserve University Department of Computer and Data Sciences ClevelandOH44106 United States Şişli Hamidiye Etfal Training and Research Hospital Emergency Department Istanbul35371 Turkey Des Moines University Osteopathic Medicine and Public Health Des MoinesIA50312 United States Uniformed Services University Neuroscience Program WashingtonDC20814 United States University of Akron Department of Psychology AkronOH44325 United States Case Western Reserve University Center for Proteomics & Bioinformatics ClevelandOH44106 United States Case Western Reserve University Department of Psychiatry ClevelandOH44106 United States University Hospitals Family Medicine ClevelandOH44106 United States

Intimate partner violence (IPV) is often studied as a problem that predominantly affects younger women. However, studies show that older women are also frequently victims of abuse even though the physical effects of abuse are harder to detect. In this study, we mined the electronic health records (EHR) available through IBM Explorys to identify health correlates of IPV that are specific to older women. Our analyses suggested that diagnostic terms that are co-morbid with IPV in older women are dominated by substance abuse and associated toxicities. When we considered differential co-morbidity, i.e., terms that are significantly more associated with IPV in older women compared to younger women, we identified terms spanning mental health issues, musculoskeletal issues, neoplasms, and disorders of various organ systems including skin, ears, nose and throat. Our findings provide pointers for further investigation in understanding the health effects of IPV among older women, as well as potential markers that can be used for screening IPV. © 2022, CC BY-NC-SA.

关键词： Records management

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Characterization of primary Sjögren's syndrome in the Taiwan Han population through a genome-wide association study and polygenic risk score analysis

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Clinical Immunology 2024年 269卷 110381-110381页

作者： Liu, Ting-Yuan Lin, Min-Rou Lu, Hsing-Fang Chen, Yu-Chia Lin, Hui-Ju Chou, Wan-Hsuan Wei, Chun-Yu Palupi, Poppy Diah Liao, Chi-Chou Chang, Yen-Ting Chang, Wei-Chiao Tsai, Fuu-Jen Department of Medical Research China Medical University Hospital China Medical University Taichung 40447 Taiwan Department of Clinical Pharmacy School of Pharmacy Taipei Medical University Taipei 110 Taiwan Department of Ophthalmology Eye Center China Medical University Hospital Taichung 40447 Taiwan Master Program in Clinical Genomics and Proteomics School of Pharmacy Taipei Medical University Taipei 110 Taiwan Core Laboratory of Neoantigen Analysis for Personalized Cancer Vaccine Office of R&D Taipei Medical University Taipei 110 Taiwan Integrative Research Center in Critical Care Wanfang Hospital Taipei Medical University Taipei 116 Taiwan Department of Pharmacy Wan Fang Hospital Taipei Medical University Taipei 110 Taiwan Department of Pharmacology National Defense Medical Center Taipei 110 Taiwan Department of Medical Research China Medical University Hospital Taichung 40402 Taiwan School of Chinese Medicine China Medical University Taichung 40402 Taiwan Division of Pediatric Medical Genetics Children's Hospital of China Medical University Taichung 40447 Taiwan Department of Biotechnology and Bioinformatics Asia University Taichung 41354 Taiwan

Background: Sjögren's syndrome (SS) is an autoimmune disorder that primarily affects the exocrine glands, leading to dryness of mucous membranes and systemic manifestations. This study aimed to identify genetic markers associated with primary SS (pSS) in the Taiwan Han population through a hospital-based genome-wide association study (GWAS) and polygenic risk score (PRS) analysis, addressing the lack of genetic research. Results: This study included 11,390 patients diagnosed with pSS and 113,900 controls. GWAS identified one known locus and eight novel loci. Known HLA alleles, including HLA-DRB1*15:01 and HLA-DQA1*03:01, were successfully replicated in a consistent effect direction. PRS analysis revealed that several autoimmune diseases share similar genetic backgrounds with pSS, including rheumatoid arthritis and systemic lupus erythematosus. Conclusion: This study represents the largest cohort to date on the genetics of pSS in the Taiwan Han population. Our findings provide valuable insights into the pathogenesis of pSS and emphasize the comorbidities associated with it as an autoimmune disease. © 2024

关键词： Gene polymorphism Genome-wide association study (GWAS) Human leukocyte antigen (HLA) Phenome-wide association study (PheWAS) Polygenic risk score (PRS) Sjögren's syndrome

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Democratising Knowledge Representation with BioCypher

arXiv

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arXiv 2022年

作者： Lobentanzer, Sebastian Aloy, Patrick Baumbach, Jan Bohar, Balazs Charoentong, Pornpimol Danhauser, Katharina Doğan, Tunca Dreo, Johann Dunham, Ian Fernandez-Torras, Adrià Gyori, Benjamin M. Hartung, Michael Hoyt, Charles Tapley Klein, Christoph Korcsmaros, Tamas Maier, Andreas Mann, Matthias Ochoa, David Pareja-Lorente, Elena Popp, Ferdinand Preusse, Martin Probul, Niklas Schwikowski, Benno Sen, Bünyamin Strauss, Maximilian T. Turei, Denes Ulusoy, Erva Heidrun Wodke, Judith Andrea Saez-Rodriguez, Julio Heidelberg University Faculty of Medicine Heidelberg University Hospital Institute for Computational Biomedicine Bioquant Heidelberg Germany The Barcelona Institute of Science and Technology Catalonia Barcelona Spain Catalonia Barcelona Spain Institute for Computational Systems Biology University of Hamburg Germany Earlham Institute Norwich United Kingdom Biological Research Centre Szeged Hungary Heidelberg University Im Neuenheimer Feld 267 Heidelberg69120 Germany Im Neuenheimer Feld 460 Heidelberg69120 Germany Department of Pediatrics Dr. von Hauner Children’s Hospital University Hospital LMU Munich Germany Biological Data Science Lab Department of Computer Engineering Hacettepe University Ankara Turkey Department of Bioinformatics Graduate School of Health Sciences Hacettepe University Ankara Turkey Computational Systems Biomedicine Lab Department of Computational Biology Institut Pasteur Université Paris Cité Paris France Bioinformatics and Biostatistics Hub Institut Pasteur Université Paris Cité Paris France Wellcome Genome Campus Cambridgeshire HinxtonCB10 1SD United Kingdom Open Targets Wellcome Genome Campus Cambridgeshire HinxtonCB10 1SD United Kingdom Laboratory of Systems Pharmacology Harvard Medical School Boston United States Imperial College London London United Kingdom Quadram Institute Bioscience Norwich United Kingdom Proteomics Program Novo Nordisk Foundation Centre for Protein Research University of Copenhagen Copenhagen Denmark Department of Proteomics and Signal Transduction Max Planck Institute of Biochemistry Martinsried Germany Im Neuenheimer Feld 460 Heidelberg69120 Germany Neuherberg Germany Medical Informatics Laboratory University Medicine Greifswald Germany

Standardising the representation of biomedical knowledge among all researchers is an insurmountable task, hindering the effectiveness of many computational methods. To facilitate harmonisation and interoperability despite this fundamental challenge, we propose to standardise the framework of knowledge graph creation instead. We implement this standardisation in BioCypher, a FAIR (findable, accessible, interoperable, reusable) framework to transparently build biomedical knowledge graphs while preserving provenances of the source data. Mapping the knowledge onto biomedical ontologies helps to balance the needs for harmonisation, human and machine readability, and ease of use and accessibility to nonspecialist researchers. We demonstrate the usefulness of this framework on a variety of use cases, from maintenance of task-specific knowledge stores, to interoperability between biomedical domains, to on-demand building of task-specific knowledge graphs for federated learning. BioCypher (https://***) frees up valuable developer time;we encourage further development and usage by the community. © 2022, CC BY-NC-ND.

关键词： Ontology

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The proteogenomic subtypes of acute myeloid leukemia

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Cancer Cell 2022年第3期40卷 301-317.e12页

作者： Jayavelu, Ashok Kumar Wolf, Sebastian Buettner, Florian Alexe, Gabriela Häupl, Björn Comoglio, Federico Schneider, Constanze Doebele, Carmen Fuhrmann, Dominik C. Wagner, Sebastian Donato, Elisa Andresen, Carolin Wilke, Anne C. Zindel, Alena Jahn, Dominique Splettstoesser, Bianca Plessmann, Uwe Münch, Silvia Abou-El-Ardat, Khali Makowka, Philipp Acker, Fabian Enssle, Julius C. Cremer, Anjali Schnütgen, Frank Kurrle, Nina Chapuy, Björn Löber, Jens Hartmann, Sylvia Wild, Peter J. Wittig, Ilka Hübschmann, Daniel Kaderali, Lars Cox, Jürgen Brüne, Bernhard Röllig, Christoph Thiede, Christian Steffen, Björn Bornhäuser, Martin Trumpp, Andreas Urlaub, Henning Stegmaier, Kimberly Serve, Hubert Mann, Matthias Oellerich, Thomas Department of Proteomics and Signal Transduction Max Planck Institute of Biochemistry Martinsried Germany Department of Medicine II Hematology/Oncology University Hospital Frankfurt Goethe University Theodor-Stern-Kai 7 Frankfurt Germany German Cancer Consortium (DKTK) Partner Site Frankfurt/Mainz and German Cancer Research Center (DKFZ) Heidelberg Germany Clinical Cooperation Unit Pediatric Leukemia DKFZ and Department of Pediatric Oncology Hematology and Immunology University of Heidelberg Germany Department of Medicine University Hospital Frankfurt Goethe University Frankfurt Germany Division of Hematology/Oncology Department of Pediatric Oncology Dana-Farber Cancer Institute and Boston Children's Hospital Boston MA United States enGene Statistics GmbH Basel Switzerland Department of Biochemistry I Goethe University Frankfurt Germany Division of Stem Cells and Cancer German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance Heidelberg Germany Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH) Heidelberg Germany Bioanalytical Mass Spectrometry Group Max Planck Institute for Biophysical Chemistry Göttingen Germany Department of Medical Hematology and Oncology University Medical Center Göttingen Göttingen Germany Dr. Senckenberg Institute of Pathology University Hospital Frankfurt Frankfurt Germany Functional Proteomics Institute of Cardiovascular Physiology Goethe University Frankfurt Germany Pattern Recognition and Digital Medicine Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM) Heidelberg Germany Computational Oncology Molecular Precision Oncology Program National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ) Heidelberg Germany Institute of Bioinformatics University Medicine Greifswald Greifswald Germany Computational Systems Biochemistry Research Group Max Planck Institute of Biochemistry Martinsried Germany Department of Internal Medicine

Acute myeloid leukemia (AML) is an aggressive blood cancer with a poor prognosis. We report a comprehensive proteogenomic analysis of bone marrow biopsies from 252 uniformly treated AML patients to elucidate the molecular pathophysiology of AML in order to inform future diagnostic and therapeutic approaches. In addition to in-depth quantitative proteomics, our analysis includes cytogenetic profiling and DNA/RNA sequencing. We identify five proteomic AML subtypes, each reflecting specific biological features spanning genomic boundaries. Two of these proteomic subtypes correlate with patient outcome, but none is exclusively associated with specific genomic aberrations. Remarkably, one subtype (Mito-AML), which is captured only in the proteome, is characterized by high expression of mitochondrial proteins and confers poor outcome, with reduced remission rate and shorter overall survival on treatment with intensive induction chemotherapy. Functional analyses reveal that Mito-AML is metabolically wired toward stronger complex I-dependent respiration and is more responsive to treatment with the BCL2 inhibitor venetoclax. © 2022 Elsevier Inc.

关键词： acute myeloid leukemia BCL-2 inhibitor chemotherapy mitochondrial oxidative phosphorylation multi-omics data integration proteogenomics proteomics venetoclax

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A systems biology approach uncovers novel disease mechanisms in age-related macular degeneration

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Cell Genomics 2023年第6期3卷 100302-100302页

作者： Orozco, Luz D. Owen, Leah A. Hofmann, Jeffrey Stockwell, Amy D. Tao, Jianhua Haller, Susan Mukundan, Vineeth T. Clarke, Christine Lund, Jessica Sridhar, Akshayalakshmi Mayba, Oleg Barr, Julie L. Zavala, Rylee A. Graves, Elijah C. Zhang, Charles Husami, Nadine Finley, Robert Au, Elizabeth Lillvis, John H. Farkas, Michael H. Shakoor, Akbar Sherva, Richard Kim, Ivana K. Kaminker, Joshua S. Townsend, Michael J. Farrer, Lindsay A. Yaspan, Brian L. Chen, Hsu-Hsin DeAngelis, Margaret M. Department of Bioinformatics and Computational Biology Genentech South San Francisco 94080 CA United States Department of Ophthalmology and Visual Sciences University of Utah School of Medicine The University of Utah Salt Lake City 84132 UT United States Department of Population Health Sciences University of Utah School of Medicine The University of Utah Salt Lake City 84132 UT United States Department of Obstetrics and Gynecology University of Utah School of Medicine The University of Utah Salt Lake City 84132 UT United States Department of Ophthalmology Ross Eye Institute Jacobs School of Medicine and Biomedical Sciences State University of New York University at Buffalo Buffalo 14203 NY United States Department of Pathology Genentech South San Francisco 94080 CA United States Department of Human Genetics Genentech South San Francisco 94080 CA United States Departments of Microchemistry Proteomics and Lipidomics Genentech South San Francisco 94080 CA United States Department of Human Pathobiology & OMNI Reverse Translation Genentech South San Francisco 94080 CA United States Neuroscience Graduate Program Jacobs School of Medicine and Biomedical Sciences State University of New York University at Buffalo Buffalo 14203 NY United States Department of Biochemistry Jacobs School of Medicine and Biomedical Sciences State University of New York University at Buffalo Buffalo 14203 NY United States Veterans Administration Western New York Healthcare System Buffalo 14212 NY United States Department of Medicine Biomedical Genetics Boston University School of Medicine Boston 02118 MA United States Retina Service Massachusetts Eye & Ear Department of Ophthalmology Harvard Medical School Boston 02114 MA United States Genetics Genomics and Bioinformatics Graduate Program Jacobs School of Medicine and Biomedical Sciences State University of New York University at Buffalo Buffalo 14203 NY United States

Age-related macular degeneration (AMD) is a leading cause of blindness, affecting 200 million people worldwide. To identify genes that could be targeted for treatment, we created a molecular atlas at different stages of AMD. Our resource is comprised of RNA sequencing (RNA-seq) and DNA methylation microarrays from bulk macular retinal pigment epithelium (RPE)/choroid of clinically phenotyped normal and AMD donor eyes (n = 85), single-nucleus RNA-seq (164,399 cells), and single-nucleus assay for transposase-accessible chromatin (ATAC)-seq (125,822 cells) from the retina, RPE, and choroid of 6 AMD and 7 control donors. We identified 23 genome-wide significant loci differentially methylated in AMD, over 1,000 differentially expressed genes across different disease stages, and an AMD Müller state distinct from normal or gliosis. Chromatin accessibility peaks in genome-wide association study (GWAS) loci revealed putative causal genes for AMD, including HTRA1 and C6orf223. Our systems biology approach uncovered molecular mechanisms underlying AMD, including regulators of WNT signaling, FRZB and TLE2, as mechanistic players in disease. © 2023 The Authors

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RETRACTED ARTICLE: IspH inhibitors kill Gram-negative bacteria and mobilize immune clearanceAssociated Content

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Nature 2021年第7843期589卷

作者： Kumar Sachin Singh Rishabh Sharma Prashanthi Vonteddu Anjana Sundarrajan Hyeree Choi Kar Muthumani Farokh Dotiwala Poli Adi Narayana Reddy Madeline Good Maureen E. Murphy Rajasekharan Somasundaram Meenhard Herlyn Joseph M. Salvino Andrew Kossenkov Aaron R. Goldman Hsin-Yao Tang Maxim Totrov Joel Cassel Vaccine and Immunotherapy Center The Wistar Institute Philadelphia PA USA Program in Molecular and Cellular Oncogenesis The Wistar Institute Philadelphia PA USA Molecular Screening and Protein Expression Facility The Wistar Institute Philadelphia PA USA Bioinformatics Facility The Wistar Institute Philadelphia PA USA Proteomics and Metabolomics Facility The Wistar Institute Philadelphia PA USA Molsoft San Diego CA USA

Isoprenoids are vital for all organisms, in which they maintain membrane stability and support core functions such as respiration1. IspH, an enzyme in the methyl erythritol phosphate pathway of isoprenoid synthesis, is essential for Gram-negative bacteria, mycobacteria and apicomplexans2,3. Its substrate, (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP), is not produced in metazoans, and in humans and other primates it activates cytotoxic Vγ9Vδ2 T cells at extremely low concentrations4,5,6. Here we describe a class of IspH inhibitors and refine their potency to nanomolar levels through structure-guided analogue design. After modification of these compounds into prodrugs for delivery into bacteria, we show that they kill clinical isolates of several multidrug-resistant bacteria—including those from the generaAcinetobacter,Pseudomonas,Klebsiella,Enterobacter,Vibrio,Shigella,Salmonella,Yersinia,MycobacteriumandBacillus—yet are relatively non-toxic to mammalian cells. Proteomic analysis reveals that bacteria treated with these prodrugs resemble those after conditional IspH knockdown. Notably, these prodrugs also induce the expansion and activation of human Vγ9Vδ2 T cells in a humanized mouse model of bacterial infection. The prodrugs we describe here synergize the direct killing of bacteria with a simultaneous rapid immune response by cytotoxic γδ T cells, which may limit the increase of antibiotic-resistant bacterial populations.

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