Pub Date : 2025-10-31DOI: 10.1038/s41564-025-02153-x
Ryan S. Roark, Andrew J. Schaub, Wei Shi, Maple Wang, Fabiana A. Bahna, Jordan E. Becker, Andrea Biju, Sue Chong, Haijuan Du, Yicheng Guo, Hsiang Hong, Phinikoula S. Katsamba, Seetha M. Mannepalli, Adam S. Olia, Li Ou, Sarah K. Rubin, Yosef Sabo, Mehin Suleiman, Malcolm L. Wells, Baoshan Zhang, Cheng Cheng, Anum Glasgow, David D. Ho, Yaoxing Huang, Theodore C. Pierson, Reda Rawi, Tongqing Zhou, Lawrence Shapiro, Peter D. Kwong
Glycoprotein B (gB) refolds between prefusion and postfusion conformations to facilitate herpesvirus entry into host cells. However, the isolation of prefusion-specific neutralizing antibodies, effective against other viral entry machines, has been challenging. Here we describe stabilization of the prefusion gB ectodomain from herpes simplex virus 1 (HSV-1), determine ectodomain structures at 2.9- to 4.1-Å resolution using cryogenic electron microscopy (cryo-EM) and isolate a prefusion-specific gB-neutralizing antibody termed WS.HSV-1.24. Murine immunization with gB stabilized in the prefusion conformation induced high titres of antibodies binding to both prefusion and postfusion gB, but—most notably—without measurable serum neutralization. Accessibility analysis revealed iso-surface exposure, with accessible surfaces on prefusion HSV-1 gB also exposed on postfusion gB. Structural analysis suggested substantial plasticity, with regions that refolded between pre- and postfusion conformations relegated to domain interfaces with limited accessibility; indeed, WS.HSV-1.24 recognized a domain-interface refolding region to facilitate neutralization. We propose that prefusion HSV-1 gB evades neutralization by most antibodies through an iso-surface display that is coupled to structural plasticity. Cryo-EM structures of the stabilized prefusion conformation of the glycoprotein B ectodomain—the HSV-1 entry machine—identify a prefusion-specific neutralizing antibody and reveal how prefusion glycoprotein B may evade antibody-mediated neutralization.
{"title":"Prefusion structure, evasion and neutralization of HSV-1 glycoprotein B","authors":"Ryan S. Roark, Andrew J. Schaub, Wei Shi, Maple Wang, Fabiana A. Bahna, Jordan E. Becker, Andrea Biju, Sue Chong, Haijuan Du, Yicheng Guo, Hsiang Hong, Phinikoula S. Katsamba, Seetha M. Mannepalli, Adam S. Olia, Li Ou, Sarah K. Rubin, Yosef Sabo, Mehin Suleiman, Malcolm L. Wells, Baoshan Zhang, Cheng Cheng, Anum Glasgow, David D. Ho, Yaoxing Huang, Theodore C. Pierson, Reda Rawi, Tongqing Zhou, Lawrence Shapiro, Peter D. Kwong","doi":"10.1038/s41564-025-02153-x","DOIUrl":"10.1038/s41564-025-02153-x","url":null,"abstract":"Glycoprotein B (gB) refolds between prefusion and postfusion conformations to facilitate herpesvirus entry into host cells. However, the isolation of prefusion-specific neutralizing antibodies, effective against other viral entry machines, has been challenging. Here we describe stabilization of the prefusion gB ectodomain from herpes simplex virus 1 (HSV-1), determine ectodomain structures at 2.9- to 4.1-Å resolution using cryogenic electron microscopy (cryo-EM) and isolate a prefusion-specific gB-neutralizing antibody termed WS.HSV-1.24. Murine immunization with gB stabilized in the prefusion conformation induced high titres of antibodies binding to both prefusion and postfusion gB, but—most notably—without measurable serum neutralization. Accessibility analysis revealed iso-surface exposure, with accessible surfaces on prefusion HSV-1 gB also exposed on postfusion gB. Structural analysis suggested substantial plasticity, with regions that refolded between pre- and postfusion conformations relegated to domain interfaces with limited accessibility; indeed, WS.HSV-1.24 recognized a domain-interface refolding region to facilitate neutralization. We propose that prefusion HSV-1 gB evades neutralization by most antibodies through an iso-surface display that is coupled to structural plasticity. Cryo-EM structures of the stabilized prefusion conformation of the glycoprotein B ectodomain—the HSV-1 entry machine—identify a prefusion-specific neutralizing antibody and reveal how prefusion glycoprotein B may evade antibody-mediated neutralization.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"10 11","pages":"2966-2980"},"PeriodicalIF":19.4,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41564-025-02153-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145404561","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-31DOI: 10.1038/s41564-025-02161-x
Wangbiao Guo, Sarah Zhang, Jin Hwan Park, Venus Stanton, Merrill Asp, Helen Herrera, Jung-Shen Benny Tai, Jian Yue, Jiaqi Wang, Jiaqi Guo, Rajeev Kumar, Jack M. Botting, Shenping Wu, Jing Yan, Karl E. Klose, Fitnat H. Yildiz, Jun Liu
Motility promotes the complex life cycle and infectious capabilities of Vibrio cholerae and is driven by rotation of a single polar flagellum. The flagellar filament comprises four flagellin proteins (FlaA–D) and is covered by a membranous sheath continuous with the outer membrane. Here we combine in situ cryo-electron microscopy single-particle analysis, fluorescence microscopy and molecular genetics to determine 2.92–3.43 Å structures of the sheathed flagellar filament from intact bacteria. Our data reveal the spatial arrangement of FlaA–D, showing that FlaA localizes at the cell pole and functions as a template for filament assembly involving multiple flagellins. Unlike unsheathed flagellar filaments, the sheathed filament from V. cholerae possesses a highly conserved core but a smooth, hydrophilic surface adjacent to the membranous sheath. A tiny conformational change at the single flagellin level results in a supercoiled filament and curved membranous sheath, supporting a model wherein the filament rotates separately from the sheath, enabling the distinct motility of V. cholerae. In situ cryo-electron microscopy structures show the spatial arrangement of flagellin proteins and provide insight into mechanisms of assembly and rotation of the sheathed flagellum in Vibrio cholerae.
{"title":"Structures of the sheathed flagellum reveal mechanisms of assembly and rotation in Vibrio cholerae","authors":"Wangbiao Guo, Sarah Zhang, Jin Hwan Park, Venus Stanton, Merrill Asp, Helen Herrera, Jung-Shen Benny Tai, Jian Yue, Jiaqi Wang, Jiaqi Guo, Rajeev Kumar, Jack M. Botting, Shenping Wu, Jing Yan, Karl E. Klose, Fitnat H. Yildiz, Jun Liu","doi":"10.1038/s41564-025-02161-x","DOIUrl":"10.1038/s41564-025-02161-x","url":null,"abstract":"Motility promotes the complex life cycle and infectious capabilities of Vibrio cholerae and is driven by rotation of a single polar flagellum. The flagellar filament comprises four flagellin proteins (FlaA–D) and is covered by a membranous sheath continuous with the outer membrane. Here we combine in situ cryo-electron microscopy single-particle analysis, fluorescence microscopy and molecular genetics to determine 2.92–3.43 Å structures of the sheathed flagellar filament from intact bacteria. Our data reveal the spatial arrangement of FlaA–D, showing that FlaA localizes at the cell pole and functions as a template for filament assembly involving multiple flagellins. Unlike unsheathed flagellar filaments, the sheathed filament from V. cholerae possesses a highly conserved core but a smooth, hydrophilic surface adjacent to the membranous sheath. A tiny conformational change at the single flagellin level results in a supercoiled filament and curved membranous sheath, supporting a model wherein the filament rotates separately from the sheath, enabling the distinct motility of V. cholerae. In situ cryo-electron microscopy structures show the spatial arrangement of flagellin proteins and provide insight into mechanisms of assembly and rotation of the sheathed flagellum in Vibrio cholerae.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"10 12","pages":"3305-3314"},"PeriodicalIF":19.4,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145404562","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 : 2025-10-31DOI: 10.1038/s41564-025-02165-7
Yifei Liao, Jinjie Yan, Isabella Y. Kong, Zhixuan Li, Weiyue Ding, Sarah Clark, Davide Maestri, Tetsuya Yoshida, Lisa Giulino-Roth, Benjamin E. Gewurz
Epstein–Barr virus (EBV) infects >95% of adults and contributes to several human cancers. EBV can remain latent where viral lytic genes are silenced, precluding the use of antiviral agents such as ganciclovir. Little is known about the host factors involved in EBV latency. Here we performed a human genome-wide CRISPR–Cas9 screen in Burkitt lymphoma B cells, which identified lysine-specific histone demethylase 1 (LSD1) and its corepressors REST corepressor 1 (CoREST) and zinc finger protein 217 (ZNF217) as critical for EBV latency. Gene knockout or LSD1 inhibition triggered EBV reactivation, and the latter sensitized cells to ganciclovir cytotoxicity, including in murine tumour xenografts. Mechanistically, ZNF217 recruits LSD1 and CoREST to form a complex that binds a specific DNA motif associated with regions implicated in EBV reactivation. It removes histone 3 lysine 4 (H3K4) methylation marks and restricts host DNA looping. Alternatively, the H3K4 lysine methyltransferase 2D supports EBV lytic reactivation. Our results highlight H3K4 methylation as a major EBV lytic switch regulator and therapeutic target. The human host factors LSD1, CoREST and ZNF217 are important in maintaining Epstein–Barr virus latency, and the depletion of these factors or inhibition of LSD1 can trigger Epstein–Barr virus reactivation and sensitize infected cells to ganciclovir treatment.
{"title":"Lysine-specific histone demethylase complex restricts Epstein–Barr virus lytic reactivation","authors":"Yifei Liao, Jinjie Yan, Isabella Y. Kong, Zhixuan Li, Weiyue Ding, Sarah Clark, Davide Maestri, Tetsuya Yoshida, Lisa Giulino-Roth, Benjamin E. Gewurz","doi":"10.1038/s41564-025-02165-7","DOIUrl":"10.1038/s41564-025-02165-7","url":null,"abstract":"Epstein–Barr virus (EBV) infects >95% of adults and contributes to several human cancers. EBV can remain latent where viral lytic genes are silenced, precluding the use of antiviral agents such as ganciclovir. Little is known about the host factors involved in EBV latency. Here we performed a human genome-wide CRISPR–Cas9 screen in Burkitt lymphoma B cells, which identified lysine-specific histone demethylase 1 (LSD1) and its corepressors REST corepressor 1 (CoREST) and zinc finger protein 217 (ZNF217) as critical for EBV latency. Gene knockout or LSD1 inhibition triggered EBV reactivation, and the latter sensitized cells to ganciclovir cytotoxicity, including in murine tumour xenografts. Mechanistically, ZNF217 recruits LSD1 and CoREST to form a complex that binds a specific DNA motif associated with regions implicated in EBV reactivation. It removes histone 3 lysine 4 (H3K4) methylation marks and restricts host DNA looping. Alternatively, the H3K4 lysine methyltransferase 2D supports EBV lytic reactivation. Our results highlight H3K4 methylation as a major EBV lytic switch regulator and therapeutic target. The human host factors LSD1, CoREST and ZNF217 are important in maintaining Epstein–Barr virus latency, and the depletion of these factors or inhibition of LSD1 can trigger Epstein–Barr virus reactivation and sensitize infected cells to ganciclovir treatment.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"10 12","pages":"3290-3304"},"PeriodicalIF":19.4,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145404565","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 : 2025-10-31DOI: 10.1038/s41564-025-02191-5
Herpesviruses cause a high disease burden, yet vaccines are lacking. Developing efficacious vaccines remains challenging and more research is needed to address this unmet public health priority.
{"title":"The complex path towards herpesvirus vaccines","authors":"","doi":"10.1038/s41564-025-02191-5","DOIUrl":"10.1038/s41564-025-02191-5","url":null,"abstract":"Herpesviruses cause a high disease burden, yet vaccines are lacking. Developing efficacious vaccines remains challenging and more research is needed to address this unmet public health priority.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"10 11","pages":"2647-2648"},"PeriodicalIF":19.4,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41564-025-02191-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145407455","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-31DOI: 10.1038/s41564-025-02134-0
Peter Simmonds, Anamarija Butković, Joe Grove, Richard Mayne, Jonathon C. O. Mifsud, Martin Beer, Jens Bukh, J. Felix Drexler, Amit Kapoor, Volker Lohmann, Donald B. Smith, Jack T. Stapleton, Nikos Vasilakis, Jens H. Kuhn
Flaviviridae is a family of non-segmented positive-sense RNA viruses that includes major pathogens such as hepatitis C virus, dengue viruses and yellow fever virus. Recent large-scale metagenomic surveys have identified many RNA viruses related to members of this family, such as orthoflaviviruses and pestiviruses. These viruses diverge by having different genome lengths and configurations, and host range. Here we performed an analysis of RNA-directed RNA polymerase (RdRP) hallmark gene sequences of flaviviruses and ‘flavi-like’ viruses. We uncovered four divergent clades and multiple lineages that are congruent with phylogenies of their helicase genes, protein profile hidden Markov model profiles, and evolutionary relationships based on predicted RdRP protein structures. These results support their classification into three families (Flaviviridae, Pestiviridae and Hepaciviridae) and 12 genera in the established order Amarillovirales, with groupings correlating with genome properties and host range. This taxonomy provides a framework for future evolutionary studies on this important viral family. Analysis of RNA polymerase hallmark gene phylogenies supported by protein structure relationships of flaviviruses and ‘flavi-like’ viruses underpins the taxonomic expansion and reorganization of Flaviviridae.
{"title":"Taxonomic expansion and reorganization of Flaviviridae","authors":"Peter Simmonds, Anamarija Butković, Joe Grove, Richard Mayne, Jonathon C. O. Mifsud, Martin Beer, Jens Bukh, J. Felix Drexler, Amit Kapoor, Volker Lohmann, Donald B. Smith, Jack T. Stapleton, Nikos Vasilakis, Jens H. Kuhn","doi":"10.1038/s41564-025-02134-0","DOIUrl":"10.1038/s41564-025-02134-0","url":null,"abstract":"Flaviviridae is a family of non-segmented positive-sense RNA viruses that includes major pathogens such as hepatitis C virus, dengue viruses and yellow fever virus. Recent large-scale metagenomic surveys have identified many RNA viruses related to members of this family, such as orthoflaviviruses and pestiviruses. These viruses diverge by having different genome lengths and configurations, and host range. Here we performed an analysis of RNA-directed RNA polymerase (RdRP) hallmark gene sequences of flaviviruses and ‘flavi-like’ viruses. We uncovered four divergent clades and multiple lineages that are congruent with phylogenies of their helicase genes, protein profile hidden Markov model profiles, and evolutionary relationships based on predicted RdRP protein structures. These results support their classification into three families (Flaviviridae, Pestiviridae and Hepaciviridae) and 12 genera in the established order Amarillovirales, with groupings correlating with genome properties and host range. This taxonomy provides a framework for future evolutionary studies on this important viral family. Analysis of RNA polymerase hallmark gene phylogenies supported by protein structure relationships of flaviviruses and ‘flavi-like’ viruses underpins the taxonomic expansion and reorganization of Flaviviridae.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"10 11","pages":"3026-3037"},"PeriodicalIF":19.4,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145404560","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 : 2025-10-30DOI: 10.1038/s41564-025-02152-y
Chen Liu, Young-Jun Park, Cheng-Bao Ma, Risako Gen, Cameron Stewart, Yu-Cheng Sun, Xiao Yang, Mei-Yi Lin, Qing Xiong, Jun-Yu Si, Peng Liu, David Veesler, Huan Yan
Dipeptidyl peptidase-4 (DPP4) is an established receptor for Middle East respiratory syndrome-related coronaviruses (MERSr-CoVs), while recent studies have identified angiotensin-converting enzyme 2 (ACE2) usage in multiple merbecovirus clades. Yet, receptor usage of many genetically diverse bat MERSr-CoVs remains unclear. Here we show that broadly distributed HKU25 clade merbecoviruses use ACE2, rather than DPP4, as their receptor. Cryo-electron microscopy revealed that HsItaly2011 and VsCoV-a7 strains engage ACE2 similarly to HKU5 but with remodelled interfaces and distinct orthologue selectivity, suggesting a shared evolutionary origin of ACE2 recognition. EjCoV-3, a close relative of the DPP4-using BtCoV422, showed broad multi-species ACE2 tropism and preadaptation to human ACE2. Several ACE2 glycans and residues within or near the binding interface were identified as determinants of orthologue selectivity. These viruses remain sensitive to several broadly neutralizing antibodies and entry inhibitors, indicating potential countermeasures for future outbreaks. These findings highlight the versatility of ACE2 as a functional receptor for diverse coronaviruses. The HKU25 clade MERS-related coronaviruses with broad distribution are shown to use ACE2 as a functional receptor, revealing unexpected receptor plasticity and offering new insights into coronavirus evolution, host range and potential zoonotic risk.
{"title":"HKU25 clade MERS-related coronaviruses use ACE2 as a functional receptor","authors":"Chen Liu, Young-Jun Park, Cheng-Bao Ma, Risako Gen, Cameron Stewart, Yu-Cheng Sun, Xiao Yang, Mei-Yi Lin, Qing Xiong, Jun-Yu Si, Peng Liu, David Veesler, Huan Yan","doi":"10.1038/s41564-025-02152-y","DOIUrl":"10.1038/s41564-025-02152-y","url":null,"abstract":"Dipeptidyl peptidase-4 (DPP4) is an established receptor for Middle East respiratory syndrome-related coronaviruses (MERSr-CoVs), while recent studies have identified angiotensin-converting enzyme 2 (ACE2) usage in multiple merbecovirus clades. Yet, receptor usage of many genetically diverse bat MERSr-CoVs remains unclear. Here we show that broadly distributed HKU25 clade merbecoviruses use ACE2, rather than DPP4, as their receptor. Cryo-electron microscopy revealed that HsItaly2011 and VsCoV-a7 strains engage ACE2 similarly to HKU5 but with remodelled interfaces and distinct orthologue selectivity, suggesting a shared evolutionary origin of ACE2 recognition. EjCoV-3, a close relative of the DPP4-using BtCoV422, showed broad multi-species ACE2 tropism and preadaptation to human ACE2. Several ACE2 glycans and residues within or near the binding interface were identified as determinants of orthologue selectivity. These viruses remain sensitive to several broadly neutralizing antibodies and entry inhibitors, indicating potential countermeasures for future outbreaks. These findings highlight the versatility of ACE2 as a functional receptor for diverse coronaviruses. The HKU25 clade MERS-related coronaviruses with broad distribution are shown to use ACE2 as a functional receptor, revealing unexpected receptor plasticity and offering new insights into coronavirus evolution, host range and potential zoonotic risk.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"10 11","pages":"2860-2874"},"PeriodicalIF":19.4,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41564-025-02152-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145396919","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-30DOI: 10.1038/s41564-025-02147-9
Gregory A. Phelps, Sinem Kurt, Alexander R. Jenner, Shelby M. Anderson, Thalina D. Jayasinghe, Elizabeth C. Griffith, Carl W. Thompson, Lei Yang, Basil Wicki, Frederick K. Bright, Victoria Loudon, William C. Wright, Ashish Srivastava, Amarinder Singh, Bhargavi Thalluri, Hyunseo Park, Robin B. Lee, Anna K. Wright, Oliver Grant-Chapman, Daryl K. Conner, Brennen T. Troyer, Amy Iverson, Jason Ochoado, Vishwajeeth R. Pagala, Long Wu, Stephanie Byrum, Yingxue Fu, Zu-Fei Yuan, Anthony A. High, Bettina Schulthess, Jason W. Rosch, Paul Geeleher, Sven N. Hobbie, Lucas Boeck, Bernd Meibohm, Andres Obregon-Henao, Peter Sander, Richard E. Lee
Non-tuberculous mycobacteria are emerging pathogens with high intrinsic drug resistance. Among these, Mycobacterium abscessus is particularly refractory owing to its extensive array of resistance mechanisms. Here we introduce florfenicol amine (FF-NH2), a major metabolite of the antibiotic florfenicol, which acts as a prodrug with narrow-spectrum activity against M. abscessus−chelonae complex species. FF-NH2 leverages intrinsic M. abscessus resistance conferred by the transcription factor WhiB7. It avoids WhiB7-dependent resistance mediated by the O-acetyltransferase Cat and is activated by the WhiB7-dependent N-acetyltransferase Eis2 in a prodrug fashion to generate the active translational inhibitor FF acetyl (FF-ac). FF-NH2 induces Eis2 expression through WhiB7, creating a feed-forward bioactivation loop, which increases FF-ac accumulation and antimicrobial action. FF-NH2 displays antiresistance properties, can synergize with other antibiotics and mitigates toxicity linked to mammalian mitochondrial ribosome inhibition. Importantly, FF-NH2 demonstrated efficacy in a murine model of M. abscessus infection. These findings suggest intrinsic resistance can be exploited to develop safer and more effective treatments for this pathogen. Florfenicol amine hijacks intrinsic resistance in Mycobacterium abscessus, highlighting that antimicrobial resistance mechanisms can be harnessed for antibiotic activation.
{"title":"Prodrug florfenicol amine is activated by intrinsic resistance to target Mycobacterium abscessus","authors":"Gregory A. Phelps, Sinem Kurt, Alexander R. Jenner, Shelby M. Anderson, Thalina D. Jayasinghe, Elizabeth C. Griffith, Carl W. Thompson, Lei Yang, Basil Wicki, Frederick K. Bright, Victoria Loudon, William C. Wright, Ashish Srivastava, Amarinder Singh, Bhargavi Thalluri, Hyunseo Park, Robin B. Lee, Anna K. Wright, Oliver Grant-Chapman, Daryl K. Conner, Brennen T. Troyer, Amy Iverson, Jason Ochoado, Vishwajeeth R. Pagala, Long Wu, Stephanie Byrum, Yingxue Fu, Zu-Fei Yuan, Anthony A. High, Bettina Schulthess, Jason W. Rosch, Paul Geeleher, Sven N. Hobbie, Lucas Boeck, Bernd Meibohm, Andres Obregon-Henao, Peter Sander, Richard E. Lee","doi":"10.1038/s41564-025-02147-9","DOIUrl":"10.1038/s41564-025-02147-9","url":null,"abstract":"Non-tuberculous mycobacteria are emerging pathogens with high intrinsic drug resistance. Among these, Mycobacterium abscessus is particularly refractory owing to its extensive array of resistance mechanisms. Here we introduce florfenicol amine (FF-NH2), a major metabolite of the antibiotic florfenicol, which acts as a prodrug with narrow-spectrum activity against M. abscessus−chelonae complex species. FF-NH2 leverages intrinsic M. abscessus resistance conferred by the transcription factor WhiB7. It avoids WhiB7-dependent resistance mediated by the O-acetyltransferase Cat and is activated by the WhiB7-dependent N-acetyltransferase Eis2 in a prodrug fashion to generate the active translational inhibitor FF acetyl (FF-ac). FF-NH2 induces Eis2 expression through WhiB7, creating a feed-forward bioactivation loop, which increases FF-ac accumulation and antimicrobial action. FF-NH2 displays antiresistance properties, can synergize with other antibiotics and mitigates toxicity linked to mammalian mitochondrial ribosome inhibition. Importantly, FF-NH2 demonstrated efficacy in a murine model of M. abscessus infection. These findings suggest intrinsic resistance can be exploited to develop safer and more effective treatments for this pathogen. Florfenicol amine hijacks intrinsic resistance in Mycobacterium abscessus, highlighting that antimicrobial resistance mechanisms can be harnessed for antibiotic activation.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"10 11","pages":"2875-2891"},"PeriodicalIF":19.4,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41564-025-02147-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145396923","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-30DOI: 10.1038/s41564-025-02157-7
Karolina S. Jabbar, Sambhawa Priya, Jiawu Xu, Upasana Das Adhikari, Gleb Pishchany, Ahmed T. M. Mohamed, Joachim Johansen, Kumar Thurimella, Cristin McCabe, Hera Vlamakis, Samson Okello, Toni M. Delorey, Alexander Lankowski, Mosepele Mosepele, Mark J. Siedner, Damian R. Plichta, Douglas S. Kwon, Ramnik J. Xavier
Human immunodeficiency virus (HIV) infection alters gut microbiota composition and function, but the impact of geography and antiretroviral therapy remains unclear. Here we determined gut microbiome alterations linked to HIV infection and antiretroviral treatment in 327 individuals with HIV and 260 control participants in cohorts from Uganda, Botswana and the USA via faecal metagenomics. We found that while HIV-associated taxonomic differences were mostly site specific, changes in microbial functional pathways were broadly consistent across the cohorts and exacerbated in individuals with acquired immunodeficiency syndrome. Microbiome perturbations associated with antiretroviral medications were also geography dependent. In Botswana and Uganda, use of the non-nucleoside reverse transcriptase inhibitor efavirenz was linked to depletion of Prevotella, disruption of interspecies metabolic networks, exacerbation of systemic inflammation and atherosclerosis. Efavirenz-associated Prevotella depletion may occur through cross-inhibition of prokaryotic reverse transcriptases involved in antiphage defences, as shown by computational and in vitro experiments. These observations could inform future geography-specific and microbiome-guided therapy. Metagenomic analysis of the gut microbiome of people with human immunodeficiency virus (HIV), from three distinct cohorts, revealed infection- and antiretroviral drug-linked alterations, which may contribute to HIV-associated non-infectious comorbidities.
{"title":"Human immunodeficiency virus and antiretroviral therapies exert distinct influences across diverse gut microbiomes","authors":"Karolina S. Jabbar, Sambhawa Priya, Jiawu Xu, Upasana Das Adhikari, Gleb Pishchany, Ahmed T. M. Mohamed, Joachim Johansen, Kumar Thurimella, Cristin McCabe, Hera Vlamakis, Samson Okello, Toni M. Delorey, Alexander Lankowski, Mosepele Mosepele, Mark J. Siedner, Damian R. Plichta, Douglas S. Kwon, Ramnik J. Xavier","doi":"10.1038/s41564-025-02157-7","DOIUrl":"10.1038/s41564-025-02157-7","url":null,"abstract":"Human immunodeficiency virus (HIV) infection alters gut microbiota composition and function, but the impact of geography and antiretroviral therapy remains unclear. Here we determined gut microbiome alterations linked to HIV infection and antiretroviral treatment in 327 individuals with HIV and 260 control participants in cohorts from Uganda, Botswana and the USA via faecal metagenomics. We found that while HIV-associated taxonomic differences were mostly site specific, changes in microbial functional pathways were broadly consistent across the cohorts and exacerbated in individuals with acquired immunodeficiency syndrome. Microbiome perturbations associated with antiretroviral medications were also geography dependent. In Botswana and Uganda, use of the non-nucleoside reverse transcriptase inhibitor efavirenz was linked to depletion of Prevotella, disruption of interspecies metabolic networks, exacerbation of systemic inflammation and atherosclerosis. Efavirenz-associated Prevotella depletion may occur through cross-inhibition of prokaryotic reverse transcriptases involved in antiphage defences, as shown by computational and in vitro experiments. These observations could inform future geography-specific and microbiome-guided therapy. Metagenomic analysis of the gut microbiome of people with human immunodeficiency virus (HIV), from three distinct cohorts, revealed infection- and antiretroviral drug-linked alterations, which may contribute to HIV-associated non-infectious comorbidities.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"10 11","pages":"2720-2735"},"PeriodicalIF":19.4,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145396920","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 : 2025-10-30DOI: 10.1038/s41564-025-02148-8
Nichole A. Ginnan, Valéria Custódio, David Gopaulchan, Natalie Ford, Isai Salas-González, Dylan H. Jones, Darren M. Wells, Ângela Moreno, Gabriel Castrillo, Maggie R. Wagner
Drought alters the soil microbiota by selecting for functional traits that preserve fitness in dry conditions. Legacy effects or ecological memory refers to how past stress exposure influences microbiota responses to future environmental challenges. How precipitation legacy effects impact soil microorganisms and plants is unclear, especially in the context of subsequent drought. Here we characterized the metagenomes of six prairie soils spanning a precipitation gradient in Kansas, United States. A microbial precipitation legacy, which persisted over a 5-month-long experimental drought, mitigated the negative physiological effects of acute drought for a native wild grass species, but not for the domesticated crop species maize. RNA sequencing of roots revealed that soil microbiota with a low precipitation legacy altered expression of plant genes that mediate transpiration and intrinsic water-use efficiency during drought. Our results show how historical exposure to water stress alters soil microbiota, with consequences for future drought responses of some plant species. Metagenomes from prairie soils in Kansas, USA, show how historical exposure to water stress impacts soil microorganisms and subsequently drought responses in plants.
{"title":"Precipitation legacy effects on soil microbiota facilitate adaptive drought responses in plants","authors":"Nichole A. Ginnan, Valéria Custódio, David Gopaulchan, Natalie Ford, Isai Salas-González, Dylan H. Jones, Darren M. Wells, Ângela Moreno, Gabriel Castrillo, Maggie R. Wagner","doi":"10.1038/s41564-025-02148-8","DOIUrl":"10.1038/s41564-025-02148-8","url":null,"abstract":"Drought alters the soil microbiota by selecting for functional traits that preserve fitness in dry conditions. Legacy effects or ecological memory refers to how past stress exposure influences microbiota responses to future environmental challenges. How precipitation legacy effects impact soil microorganisms and plants is unclear, especially in the context of subsequent drought. Here we characterized the metagenomes of six prairie soils spanning a precipitation gradient in Kansas, United States. A microbial precipitation legacy, which persisted over a 5-month-long experimental drought, mitigated the negative physiological effects of acute drought for a native wild grass species, but not for the domesticated crop species maize. RNA sequencing of roots revealed that soil microbiota with a low precipitation legacy altered expression of plant genes that mediate transpiration and intrinsic water-use efficiency during drought. Our results show how historical exposure to water stress alters soil microbiota, with consequences for future drought responses of some plant species. Metagenomes from prairie soils in Kansas, USA, show how historical exposure to water stress impacts soil microorganisms and subsequently drought responses in plants.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"10 11","pages":"2823-2844"},"PeriodicalIF":19.4,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41564-025-02148-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145396921","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-29DOI: 10.1038/s41564-025-02160-y
Anna Konovalova
β-Barrel assembly machinery (BAM) structures from Bacteroidota reveal unexpected diversity in BAM architecture by identifying unique subunits that function at the cell surface.
{"title":"Bam complex redefined in Bacteroidota","authors":"Anna Konovalova","doi":"10.1038/s41564-025-02160-y","DOIUrl":"10.1038/s41564-025-02160-y","url":null,"abstract":"β-Barrel assembly machinery (BAM) structures from Bacteroidota reveal unexpected diversity in BAM architecture by identifying unique subunits that function at the cell surface.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"10 11","pages":"2653-2655"},"PeriodicalIF":19.4,"publicationDate":"2025-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145381933","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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