Pub Date : 2025-01-15DOI: 10.1016/j.chembiol.2024.12.013
Cong Shen, Aldo I. Salazar-Morales, Wonhyeuk Jung, Joey Erwin, Yangqi Gu, Anthony Coelho, Kallol Gupta, Sibel Ebru Yalcin, Fadel A. Samatey, Nikhil S. Malvankar
Microbial extracellular electron transfer (EET) drives various globally important environmental phenomena and has biotechnology applications. Diverse prokaryotes have been proposed to perform EET via surface-displayed “nanowires” composed of multi-heme cytochromes. However, the mechanism that enables only a few cytochromes to polymerize into nanowires is unclear. Here, we identify a highly conserved omcS-companion (osc) cluster that drives the formation of cytochrome OmcS nanowires in Geobacter sulfurreducens. Through a combination of genetic, biochemical, and biophysical methods, we establish that prolyl isomerase-containing chaperon OscH, channel-like OscEFG, and β-propeller-like OscD are involved in the folding, secretion, and morphology maintenance of OmcS nanowires, respectively. OscH and OscG can interact with OmcS. Furthermore, overexpression of oscG accelerates EET by overproducing nanowires in an ATP-dependent manner. Heme loading splits OscD; ΔoscD accelerates cell growth, bundles nanowires into cables. Our findings establish the mechanism and prevalence of a specialized and modular assembly system for nanowires across phylogenetically diverse species and environments
{"title":"A widespread and ancient bacterial machinery assembles cytochrome OmcS nanowires essential for extracellular electron transfer","authors":"Cong Shen, Aldo I. Salazar-Morales, Wonhyeuk Jung, Joey Erwin, Yangqi Gu, Anthony Coelho, Kallol Gupta, Sibel Ebru Yalcin, Fadel A. Samatey, Nikhil S. Malvankar","doi":"10.1016/j.chembiol.2024.12.013","DOIUrl":"https://doi.org/10.1016/j.chembiol.2024.12.013","url":null,"abstract":"Microbial extracellular electron transfer (EET) drives various globally important environmental phenomena and has biotechnology applications. Diverse prokaryotes have been proposed to perform EET via surface-displayed “nanowires” composed of multi-heme cytochromes. However, the mechanism that enables only a few cytochromes to polymerize into nanowires is unclear. Here, we identify a highly conserved <em><u>o</u>mc<u>S</u></em>-<u>c</u>ompanion (<em>osc</em>) cluster that drives the formation of cytochrome OmcS nanowires in <em>Geobacter sulfurreducens</em>. Through a combination of genetic, biochemical, and biophysical methods, we establish that prolyl isomerase-containing chaperon OscH, channel-like OscEFG, and β-propeller-like OscD are involved in the folding, secretion, and morphology maintenance of OmcS nanowires, respectively. OscH and OscG can interact with OmcS. Furthermore, overexpression of <em>oscG</em> accelerates EET by overproducing nanowires in an ATP-dependent manner. Heme loading splits OscD; Δ<em>oscD</em> accelerates cell growth, bundles nanowires into cables. Our findings establish the mechanism and prevalence of a specialized and modular assembly system for nanowires across phylogenetically diverse species and environments","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"77 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142981366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-15DOI: 10.1016/j.chembiol.2025.01.005
Beste Mutlu, Kfir Sharabi, Jee Hyung Sohn, Bo Yuan, Pedro Latorre-Muro, Xin Qin, Jin-Seon Yook, Hua Lin, Deyang Yu, João Paulo G. Camporez, Shingo Kajimura, Gerald I. Shulman, Sheng Hui, Theodore M. Kamenecka, Patrick R. Griffin, Pere Puigserver
No Abstract
没有抽象的
{"title":"Small molecules targeting selective PCK1 and PGC-1α lysine acetylation cause anti-diabetic action through increased lactate oxidation","authors":"Beste Mutlu, Kfir Sharabi, Jee Hyung Sohn, Bo Yuan, Pedro Latorre-Muro, Xin Qin, Jin-Seon Yook, Hua Lin, Deyang Yu, João Paulo G. Camporez, Shingo Kajimura, Gerald I. Shulman, Sheng Hui, Theodore M. Kamenecka, Patrick R. Griffin, Pere Puigserver","doi":"10.1016/j.chembiol.2025.01.005","DOIUrl":"https://doi.org/10.1016/j.chembiol.2025.01.005","url":null,"abstract":"No Abstract","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142981367","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-07DOI: 10.1016/j.chembiol.2024.12.006
Jian Tang, Ramkumar Moorthy, Laura E. Hirsch, Özlem Demir, Zachary D. Baker, Jordan A. Naumann, Katherine F.M. Jones, Michael J. Grillo, Ella S. Haefner, Ke Shi, Michaella J. Levy, Harshita B. Gupta, Hideki Aihara, Reuben S. Harris, Rommie E. Amaro, Nicholas M. Levinson, Daniel A. Harki
The N-Myc transcription factor, encoded by MYCN, is a mechanistically validated, yet challenging, target for neuroblastoma (NB) therapy development. In normal neuronal progenitors, N-Myc undergoes rapid degradation, while, in MYCN-amplified NB cells, Aurora kinase A (Aurora-A) binds to and stabilizes N-Myc, resulting in elevated protein levels. Here, we demonstrate that targeted protein degradation of Aurora-A decreases N-Myc levels. A potent Aurora-A degrader, HLB-0532259 (compound 4), was developed from an Aurora-A-binding ligand that engages the Aurora-A/N-Myc complex. HLB-0532259 promotes the degradation of Aurora-A, which elicits concomitant N-Myc degradation, with nanomolar potency and excellent selectivity. HLB-0532259 surpasses the cellular efficacy of established allosteric Aurora-A inhibitors, exhibits favorable pharmacokinetic properties, and elicits tumor reduction in a murine xenograft NB model. This study broadly delineates a strategy for targeting “undruggable” proteins that are reliant on accessory proteins for cellular stabilization.
{"title":"Targeting N-Myc in neuroblastoma with selective Aurora kinase A degraders","authors":"Jian Tang, Ramkumar Moorthy, Laura E. Hirsch, Özlem Demir, Zachary D. Baker, Jordan A. Naumann, Katherine F.M. Jones, Michael J. Grillo, Ella S. Haefner, Ke Shi, Michaella J. Levy, Harshita B. Gupta, Hideki Aihara, Reuben S. Harris, Rommie E. Amaro, Nicholas M. Levinson, Daniel A. Harki","doi":"10.1016/j.chembiol.2024.12.006","DOIUrl":"https://doi.org/10.1016/j.chembiol.2024.12.006","url":null,"abstract":"The N-Myc transcription factor, encoded by <em>MYCN</em>, is a mechanistically validated, yet challenging, target for neuroblastoma (NB) therapy development. In normal neuronal progenitors, N-Myc undergoes rapid degradation, while, in <em>MYCN</em>-amplified NB cells, Aurora kinase A (Aurora-A) binds to and stabilizes N-Myc, resulting in elevated protein levels. Here, we demonstrate that targeted protein degradation of Aurora-A decreases N-Myc levels. A potent Aurora-A degrader, HLB-0532259 (compound <strong>4</strong>), was developed from an Aurora-A-binding ligand that engages the Aurora-A/N-Myc complex. HLB-0532259 promotes the degradation of Aurora-A, which elicits concomitant N-Myc degradation, with nanomolar potency and excellent selectivity. HLB-0532259 surpasses the cellular efficacy of established allosteric Aurora-A inhibitors, exhibits favorable pharmacokinetic properties, and elicits tumor reduction in a murine xenograft NB model. This study broadly delineates a strategy for targeting “undruggable” proteins that are reliant on accessory proteins for cellular stabilization.","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"118 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142935250","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-06DOI: 10.1016/j.chembiol.2024.12.004
Christopher Whidbey
Microbiomes exist in ecological niches ranging from the ocean and soil to inside of larger organisms like plants and animals. Within these niches, microbes play key roles in biochemical processes that impact larger phenomena, such as biogeochemical cycling or health. By understanding of how these processes occur at the molecular level, it may be possible to develop new interventions to address global problems. The complexity of these systems poses challenges to more traditional techniques. Chemical biology can help overcome these challenges by providing tools that are broadly applicable and can obtain molecular-level information about complex systems. This primer is intended to serve as a brief introduction to chemical biology and microbiome science, to highlight some of the ways that these two disciplines complement each other, and to encourage dialog and collaboration between these fields.
{"title":"The right tool for the job: Chemical biology and microbiome science","authors":"Christopher Whidbey","doi":"10.1016/j.chembiol.2024.12.004","DOIUrl":"https://doi.org/10.1016/j.chembiol.2024.12.004","url":null,"abstract":"Microbiomes exist in ecological niches ranging from the ocean and soil to inside of larger organisms like plants and animals. Within these niches, microbes play key roles in biochemical processes that impact larger phenomena, such as biogeochemical cycling or health. By understanding of how these processes occur at the molecular level, it may be possible to develop new interventions to address global problems. The complexity of these systems poses challenges to more traditional techniques. Chemical biology can help overcome these challenges by providing tools that are broadly applicable and can obtain molecular-level information about complex systems. This primer is intended to serve as a brief introduction to chemical biology and microbiome science, to highlight some of the ways that these two disciplines complement each other, and to encourage dialog and collaboration between these fields.","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"38 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142929676","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Proteolysis targeting chimeras (PROTACs) are bifunctional molecules that induce selective protein degradation by linking an E3 ubiquitin ligase enzyme to a target protein. This approach allows scope for targeting “undruggable” proteins, and several PROTACs have reached the stage of clinical candidates. However, the roles of cellular transmembrane transporters in PROTAC uptake and efflux remain underexplored. Here, we utilized transporter-focused genetic screens to identify the ATP-binding cassette transporter ABCC1/MRP1 as a key PROTAC resistance factor. Unlike the previously identified inducible PROTAC exporter ABCB1/MDR1, ABCC1 is highly expressed among cancers of various origins and constitutively restricts PROTAC bioavailability. Moreover, in a genome-wide PROTAC resistance screen, we identified candidates involved in processes such as ubiquitination, mTOR signaling, and apoptosis as genetic factors involved in PROTAC resistance. In summary, our findings reveal ABCC1 as a crucial constitutively active efflux pump limiting PROTAC efficacy in various cancer cells, offering insights for overcoming drug resistance.
{"title":"The efflux pump ABCC1/MRP1 constitutively restricts PROTAC sensitivity in cancer cells","authors":"Gernot Wolf, Conner Craigon, Shao Thing Teoh, Patrick Essletzbichler, Svenja Onstein, Diane Cassidy, Esther C.H. Uijttewaal, Vojtech Dvorak, Yuting Cao, Ariel Bensimon, Ulrich Elling, Alessio Ciulli, Giulio Superti-Furga","doi":"10.1016/j.chembiol.2024.11.009","DOIUrl":"https://doi.org/10.1016/j.chembiol.2024.11.009","url":null,"abstract":"Proteolysis targeting chimeras (PROTACs) are bifunctional molecules that induce selective protein degradation by linking an E3 ubiquitin ligase enzyme to a target protein. This approach allows scope for targeting “undruggable” proteins, and several PROTACs have reached the stage of clinical candidates. However, the roles of cellular transmembrane transporters in PROTAC uptake and efflux remain underexplored. Here, we utilized transporter-focused genetic screens to identify the ATP-binding cassette transporter ABCC1/MRP1 as a key PROTAC resistance factor. Unlike the previously identified inducible PROTAC exporter ABCB1/MDR1, ABCC1 is highly expressed among cancers of various origins and constitutively restricts PROTAC bioavailability. Moreover, in a genome-wide PROTAC resistance screen, we identified candidates involved in processes such as ubiquitination, mTOR signaling, and apoptosis as genetic factors involved in PROTAC resistance. In summary, our findings reveal ABCC1 as a crucial constitutively active efflux pump limiting PROTAC efficacy in various cancer cells, offering insights for overcoming drug resistance.","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"82 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142917462","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-02DOI: 10.1016/j.chembiol.2024.12.002
Zher Yin Tan, Joel K.A. Adade, Xiebin Gu, Cody J.S. Hecht, Michael Salcius, Bingqi Tong, Shuang Liu, Seungmin Hwang, Frédéric J. Zécri, Daniel B. Graham, Stuart L. Schreiber, Ramnik J. Xavier
Chemical inducers of proximity (CIPs) are molecules that recruit one protein to another and introduce new functionalities toward modulating protein states and activities. While CIP-mediated recruitment of E3 ligases is widely exploited for the development of degraders, other therapeutic modalities remain underexplored. We describe a non-degrader CIP-DNA-encoded library (CIP-DEL) that recruits FKBP12 to target proteins using non-traditional acyclic structures, with an emphasis on introducing stereochemically diverse and rigid connectors to attach the combinatorial library. We deployed this strategy to modulate ATG16L1 T300A, which confers genetic susceptibility to Crohn’s disease (CD), and identified a compound that stabilizes the variant protein against caspase-3 (Casp3) cleavage in a FKBP12-independent manner. We demonstrate in cellular models that this compound potentiates autophagy, and reverses the xenophagy defects as well as increased cytokine secretion characteristic of ATG16L1 T300A. This study provides a platform to access unexplored chemical space for CIP design to develop therapeutic modalities guided by human genetics.
化学接近诱导剂（Chemical inductors of proximity, cip）是一种将一种蛋白质招募到另一种蛋白质并引入新功能来调节蛋白质状态和活性的分子。虽然cip介导的E3连接酶募集被广泛用于降解物的开发，但其他治疗方式仍未得到充分探索。我们描述了一个非降解的cip - dna编码文库（CIP-DEL），它使用非传统的无环结构招募FKBP12来靶向蛋白质，重点是引入立体化学多样性和刚性连接器来连接组合文库。我们采用这种策略来调节ATG16L1 T300A，它赋予克罗恩病（CD）的遗传易感性，并鉴定了一种化合物，该化合物以不依赖于fkbp12的方式稳定变异蛋白，防止Casp3切割。我们在细胞模型中证明，这种化合物增强了自噬，逆转了ATG16L1 T300A的异种吞噬缺陷以及增加的细胞因子分泌特征。这项研究为CIP设计提供了一个未经探索的化学空间，以开发由人类遗传学指导的治疗方式。
{"title":"Development of an FKBP12-recruiting chemical-induced proximity DNA-encoded library and its application to discover an autophagy potentiator","authors":"Zher Yin Tan, Joel K.A. Adade, Xiebin Gu, Cody J.S. Hecht, Michael Salcius, Bingqi Tong, Shuang Liu, Seungmin Hwang, Frédéric J. Zécri, Daniel B. Graham, Stuart L. Schreiber, Ramnik J. Xavier","doi":"10.1016/j.chembiol.2024.12.002","DOIUrl":"https://doi.org/10.1016/j.chembiol.2024.12.002","url":null,"abstract":"Chemical inducers of proximity (CIPs) are molecules that recruit one protein to another and introduce new functionalities toward modulating protein states and activities. While CIP-mediated recruitment of E3 ligases is widely exploited for the development of degraders, other therapeutic modalities remain underexplored. We describe a non-degrader CIP-DNA-encoded library (CIP-DEL) that recruits FKBP12 to target proteins using non-traditional acyclic structures, with an emphasis on introducing stereochemically diverse and rigid connectors to attach the combinatorial library. We deployed this strategy to modulate <em>ATG16L1</em> T300A, which confers genetic susceptibility to Crohn’s disease (CD), and identified a compound that stabilizes the variant protein against caspase-3 (Casp3) cleavage in a FKBP12-independent manner. We demonstrate in cellular models that this compound potentiates autophagy, and reverses the xenophagy defects as well as increased cytokine secretion characteristic of <em>ATG16L1</em> T300A. This study provides a platform to access unexplored chemical space for CIP design to develop therapeutic modalities guided by human genetics.","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"16 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142912189","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-30DOI: 10.1016/j.chembiol.2024.12.003
Jianjun Yu, Huijie Liu, Rui Gao, Tao V. Wang, Chenggang Li, Yuxiang Liu, Lu Yang, Ying Xu, Yunfeng Cui, Chenxi Jia, Juan Huang, Peng R. Chen, Yi Rao
Research into mechanisms underlying sleep traditionally relies on electrophysiology and genetics. Because sleep can only be measured on whole animals by behavioral observations and physical means, no sleep research was initiated by biochemical and chemical biological approaches. We used phosphorylation sites of kinases important for sleep as targets for biochemical and chemical biological approaches. Sleep was increased in mice carrying a threonine-to-alanine substitution at residue T469 of salt-inducible kinase 3 (SIK3). Our biochemical purification and photo-crosslinking revealed calcineurin (CaN) dephosphorylation, both in vitro and in vivo, of SIK3 at T469 and S551, but not T221. Knocking down CaN regulatory subunit reduced daily sleep by more than 5 h, exceeding all known mouse mutants. Our work uncovered a critical physiological role for CaN in sleep and pioneered biochemical purification and chemical biology as effective approaches to study sleep.
{"title":"Calcineurin: An essential regulator of sleep revealed by biochemical, chemical biological, and genetic approaches","authors":"Jianjun Yu, Huijie Liu, Rui Gao, Tao V. Wang, Chenggang Li, Yuxiang Liu, Lu Yang, Ying Xu, Yunfeng Cui, Chenxi Jia, Juan Huang, Peng R. Chen, Yi Rao","doi":"10.1016/j.chembiol.2024.12.003","DOIUrl":"https://doi.org/10.1016/j.chembiol.2024.12.003","url":null,"abstract":"Research into mechanisms underlying sleep traditionally relies on electrophysiology and genetics. Because sleep can only be measured on whole animals by behavioral observations and physical means, no sleep research was initiated by biochemical and chemical biological approaches. We used phosphorylation sites of kinases important for sleep as targets for biochemical and chemical biological approaches. Sleep was increased in mice carrying a threonine-to-alanine substitution at residue T469 of salt-inducible kinase 3 (SIK3). Our biochemical purification and photo-crosslinking revealed calcineurin (CaN) dephosphorylation, both <em>in vitro</em> and <em>in vivo</em>, of SIK3 at T469 and S551, but not T221. Knocking down CaN regulatory subunit reduced daily sleep by more than 5 h, exceeding all known mouse mutants. Our work uncovered a critical physiological role for CaN in sleep and pioneered biochemical purification and chemical biology as effective approaches to study sleep.","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"7 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142902000","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-27DOI: 10.1016/j.chembiol.2024.12.001
Bradley E. Poulsen, Thulasi Warrier, Sulyman Barkho, Josephine Bagnall, Keith P. Romano, Tiantian White, Xiao Yu, Tomohiko Kawate, Phuong H. Nguyen, Kyra Raines, Kristina Ferrara, A. Lorelei Golas, Michael FitzGerald, Andras Boeszoermenyi, Virendar Kaushik, Michael Serrano-Wu, Noam Shoresh, Deborah T. Hung
The surge of antimicrobial resistance threatens efficacy of current antibiotics, particularly against Pseudomonas aeruginosa, a highly resistant gram-negative pathogen. The asymmetric outer membrane (OM) of P. aeruginosa combined with its array of efflux pumps provide a barrier to xenobiotic accumulation, thus making antibiotic discovery challenging. We adapted PROSPECT, a target-based, whole-cell screening strategy, to discover small molecule probes that kill P. aeruginosa mutants depleted for essential proteins localized at the OM. We identified BRD1401, a small molecule that has specific activity against a P. aeruginosa mutant depleted for the essential lipoprotein, OprL. Genetic and chemical biological studies identified that BRD1401 acts by targeting the OM β-barrel protein OprH to disrupt its interaction with LPS and increase membrane fluidity. Studies with BRD1401 also revealed an interaction between OprL and OprH, directly linking the OM with peptidoglycan. Thus, a whole-cell, multiplexed screen can identify species-specific chemical probes to reveal pathogen biology.
{"title":"Discovery of a Pseudomonas aeruginosa-specific small molecule targeting outer membrane protein OprH-LPS interaction by a multiplexed screen","authors":"Bradley E. Poulsen, Thulasi Warrier, Sulyman Barkho, Josephine Bagnall, Keith P. Romano, Tiantian White, Xiao Yu, Tomohiko Kawate, Phuong H. Nguyen, Kyra Raines, Kristina Ferrara, A. Lorelei Golas, Michael FitzGerald, Andras Boeszoermenyi, Virendar Kaushik, Michael Serrano-Wu, Noam Shoresh, Deborah T. Hung","doi":"10.1016/j.chembiol.2024.12.001","DOIUrl":"https://doi.org/10.1016/j.chembiol.2024.12.001","url":null,"abstract":"The surge of antimicrobial resistance threatens efficacy of current antibiotics, particularly against <em>Pseudomonas aeruginosa</em>, a highly resistant gram-negative pathogen. The asymmetric outer membrane (OM) of <em>P. aeruginosa</em> combined with its array of efflux pumps provide a barrier to xenobiotic accumulation, thus making antibiotic discovery challenging. We adapted PROSPECT, a target-based, whole-cell screening strategy, to discover small molecule probes that kill <em>P. aeruginosa</em> mutants depleted for essential proteins localized at the OM. We identified BRD1401, a small molecule that has specific activity against a <em>P. aeruginosa</em> mutant depleted for the essential lipoprotein, OprL. Genetic and chemical biological studies identified that BRD1401 acts by targeting the OM β-barrel protein OprH to disrupt its interaction with LPS and increase membrane fluidity. Studies with BRD1401 also revealed an interaction between OprL and OprH, directly linking the OM with peptidoglycan. Thus, a whole-cell, multiplexed screen can identify species-specific chemical probes to reveal pathogen biology.","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"56 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142888682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-24DOI: 10.1016/j.chembiol.2024.12.008
Ling-Yan Su, Yang Tian, Qiang Zheng, Yu Cao, Mengyu Yao, Shuangping Wang, Wen Xu, Chuyu Xi, Andrea Clocchiatti, Guangjun Nie, Hejiang Zhou
(Cell Chemical Biology 31, 1219–1230.e1–e5; June 20, 2024)
(细胞化学生物学31,1219-1230.e1-e5；2024年6月20日)
{"title":"Anti-tumor immunotherapy using engineered bacterial outer membrane vesicles fused to lysosome-targeting chimeras mediated by transferrin receptor","authors":"Ling-Yan Su, Yang Tian, Qiang Zheng, Yu Cao, Mengyu Yao, Shuangping Wang, Wen Xu, Chuyu Xi, Andrea Clocchiatti, Guangjun Nie, Hejiang Zhou","doi":"10.1016/j.chembiol.2024.12.008","DOIUrl":"https://doi.org/10.1016/j.chembiol.2024.12.008","url":null,"abstract":"(Cell Chemical Biology <em>31</em>, 1219–1230.e1–e5; June 20, 2024)","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"25 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142880173","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-19DOI: 10.1016/j.chembiol.2024.11.008
Spenser H. Stone, Jeffrey C. Rathmell, Jackie E. Bader
Obesity is a leading risk factor and a negative prognostic indicator for many cancers. In a recent issue of Science Immunology, Bagchi et al. identified that tumor-associated macrophages upregulate GPR65 in response to obesity-driven intratumor acidity resulting in reduced effector function to promote tumor growth.1
{"title":"Macrophages make “sense” of obesity-driven acidity in the TME","authors":"Spenser H. Stone, Jeffrey C. Rathmell, Jackie E. Bader","doi":"10.1016/j.chembiol.2024.11.008","DOIUrl":"https://doi.org/10.1016/j.chembiol.2024.11.008","url":null,"abstract":"Obesity is a leading risk factor and a negative prognostic indicator for many cancers. In a recent issue of <em>Science Immunology</em>, Bagchi et al. identified that tumor-associated macrophages upregulate GPR65 in response to obesity-driven intratumor acidity resulting in reduced effector function to promote tumor growth.<span><span><sup>1</sup></span></span>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"87 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849689","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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