JACS Au
DOI: 10.1021/jacsau.5c00832
Karl Ocius
Shared posts
07 Oct 16:15
[ASAP] The Unique Properties and Click Capacity of the Tetrazine Group Enable Tetrazine Allyl Acetate to Serve as a Versatile Bis-Thiol Bioconjugation and Functionalization Agent
by Hang Xu, Mengyang Chang, Yue Dong, Fangchao Bi, Hongmin Li, and Wei Wang
07 Oct 16:14
[ASAP] Advances in Proximity-Assisted Bioconjugation
by Mary Canzano and Gonçalo J. L. Bernardes
Accounts of Chemical Research
DOI: 10.1021/acs.accounts.5c00368
07 Oct 16:01
The role of innate immunity, antibiotics, and bacteriophages in the course of bacterial infections and their treatment
by Brandon A. BerryhillTeresa Gil-GilChristopher WitzanyDavid A. GoldbergNic M. VegaRoland R. RegoesBruce R. LevinaDepartment of Biology, Emory University, Atlanta, GA 30322bProgram in Microbiology and Molecular Genetics, Graduate Division of Biological and Biomedical Sciences, Laney Graduate School, Emory University, Atlanta, GA 30322cInstitute of Integrative Biology, ETH Zurich, Zurich 8092, Switzerland
Proceedings of the National Academy of Sciences, Volume 122, Issue 40, October 2025.
SignificanceCentral to our understanding of the course of bacterial infections and their treatment is the contribution of the innate immune system. We use the larvae ofGalleria mellonellato test hypothesis about the role of the innate immune system on...
SignificanceCentral to our understanding of the course of bacterial infections and their treatment is the contribution of the innate immune system. We use the larvae ofGalleria mellonellato test hypothesis about the role of the innate immune system on...
06 Oct 15:28
Cell-selective multiplexed bioorthogonal noncanonical amino acid tagging for nascent proteomics
by Conor Loynd
Nature Chemical Biology, Published online: 02 October 2025; doi:10.1038/s41589-025-02039-3
Engineered aminoacyl-tRNA synthetase (aaRS) mutants have been developed that facilitate ultrafast bioorthogonal noncanonical amino acid tagging (BONCAT) of newly synthesized proteins in diverse bacteria, including ESKAPE pathogens. The substrate polyspecificity of the aaRS mutants enables pulse-chase BONCAT and differential tagging of temporally distinct nascent proteomes in cells.
06 Oct 14:55
A dual role for PGLYRP1 in host defense and immune regulation during B. pertussis infection
by David M Rickert
bioRxiv [Preprint]. 2025 Sep 27:2025.09.26.678899. doi: 10.1101/2025.09.26.678899.
ABSTRACT
Bordetella pertussis, the etiologic agent of whooping cough, remains a serious public health concern despite widespread vaccination. Improved therapeutics and vaccines are urgently needed to treat and prevent pertussis disease. Host recognition of bacterial peptidoglycan (PGN), including B. pertussis extracellular PGN fragment tracheal cytotoxin (TCT), shapes the immune response to infection. Peptidoglycan recognition proteins (PGLYRPs) are a conserved family of innate immune molecules which bind bacterial PGN. While they function as immune signaling receptors in arthropods, PGLYRPs in mammals have thus far been primarily recognized for their bactericidal activity. Previously thought to function only as antimicrobial peptides in mammals, the immune modulatory roles of this family of peptidoglycan recognition proteins are beginning to gain greater appreciation. Peptidoglycan recognition protein 1 (PGLYRP1) is a secreted antimicrobial protein. However, its role in mammalian host defenses and immune signaling during infection with Gram-negative pathogens, such as B. pertussis, remain largely unknown. Here, we identify a dual role for PGLYRP1 in modulating host immune responses to B. pertussis. Using knockout mice, single-cell and bulk transcriptomics and functional assays, we show that PGLYRP1 has bactericidal activity against B. pertussis in vitro and promotes early bacterial control in vivo. PGLYRP1 also dampens inflammatory responses and impedes bacterial killing later in infection. Mechanistically, PGLYRP1 enhances nucleotide oligomerization domain (NOD)-1 signaling in response to TCT while suppressing NOD2- and triggering receptor expressed on myeloid cells-1 (TREM-1)-mediated inflammatory pathways. TCT-bound PGLYRP1 selectively impairs TREM-1 activation compared to PGNs from other bacteria, revealing a novel bacterial immune evasion strategy. These findings demonstrate that B. pertussis co-opts PGLYRP1 to temper inflammation and alter immune signaling, revealing a novel immune evasion mechanism of manipulating the availability and structure of their exogenous peptidoglycan, revealing implications for host-pathogen evolution, vaccine design and host-directed therapeutics.
PMID:41040336 | PMC:PMC12485853 | DOI:10.1101/2025.09.26.678899
21 Sep 18:51
[ASAP] Recent Advancements in 20S Proteasome Enhancement: Degradation of Undruggable Targets
by Sydney G. Cobb and Jetze J. Tepe
ACS Medicinal Chemistry Letters
DOI: 10.1021/acsmedchemlett.5c00451
19 Sep 14:35
Regulatory roles of intestinal CD4+ T cells in inflammation and their modulation by the intestinal microbiota
by Ziyu Ma
Gut Microbes. 2025 Dec;17(1):2560019. doi: 10.1080/19490976.2025.2560019. Epub 2025 Sep 17.
ABSTRACT
Intestinal inflammation is a major global health challenge, driving the pathogenesis of inflammatory bowel disease (IBD) and imposing a significant socioeconomic burden. Dysregulated homeostasis of intestinal CD4+ T cell subsets, particularly the imbalance between pro-inflammatory T helper cells (Th1, Th2, Th17, Th9) and regulatory T cells (Tregs), is a key trigger of intestinal inflammation. These immune cells orchestrate immune responses through distinct cytokine profiles (IFN-γ/IL-4/IL-17/IL-9 vs. IL-10/TGF-β). Recent studies highlight the pivotal role of the intestinal microbiota in regulating this immune axis via three primary mechanisms: 1, Short-chain fatty acids (SCFAs) induce epigenetic reprogramming by inhibiting HDACs, promoting Treg differentiation and inhibit the differentiation of Th17/Th9 cells; 2, Secondary bile acids (BAs) suppress Th17 polarization through FXR/TGR5/PXR signaling; 3, Tryptophan metabolites (indole, kynurenine) balance Th17/Treg ratios via AhR-IL-22 signaling. Microbial dysbiosis disrupts this network by secreting pathogen-associated molecular patterns (PAMPs), such as Lipopolysaccharide (LPS) and peptidoglycan (PG), which activate pathogen pattern recognition receptors (PRRs), such as TLR4/NOD2/NF-κb signaling, driving Th1/Th17 differentiation. This review summarizes recent advances in the microbiota-CD4+ T cell interaction and discusses therapeutic strategies to modulate the intestinal microbiota, aiming to enhance understanding of IBD pathogenesis and identify potential clinical interventions.
PMID:40963293 | PMC:PMC12452487 | DOI:10.1080/19490976.2025.2560019
19 Sep 14:33
Gut commensal Lactobacillus strain induces a balanced trained immunity phenotype to enhance vaccine efficacy through JAK-STAT-SOCS pathway
by Lingdi Niu
Probiotics Antimicrob Proteins. 2025 Sep 18. doi: 10.1007/s12602-025-10769-y. Online ahead of print.
ABSTRACT
The gut microbiota plays a complex role in immune system maturation and function. The induction of memory in innate immune cells appears to be part of a co-adaptation between the host and microbiome. As important gut commensals, certain Lactobacillus have been shown to induce innate immune memory. However, the universality, phenotypic characteristics, mechanisms of Lactobacillus-induced innate immune memory, and its potential applications in vaccine immunology remain poorly understood. Here, we discovered that specific strains of the gut commensal Lactobacillus can induce innate immune memory, resulting in a more balanced trained immunity phenotype through SOCS activation. Upon secondary stimulation, macrophages exhibited increased expression of IL-6, IL-1β, IL-10, IL-12, IFN-β, and TGF-β. Peptidoglycan and components in the secretome sensitive to pancreatic enzymes were identified as key elements in inducing trained immunity. Furthermore, mice that underwent training demonstrated rapid resistance to S. aureus infection. Additionally, Lactobacillus-induced trained immunity significantly enhanced the protective efficacy of vaccines against MRSA. Our findings demonstrate that certain Lactobacillus strains can activate non-classical trained immunity, offering potential for enhancing vaccine efficacy. Our study provides new insights into the role of some gut commensals in immune modulation and suggests a novel approach to vaccine enhancement through trained immunity induced by specific gut commensals.
PMID:40965792 | DOI:10.1007/s12602-025-10769-y
16 Sep 16:00
[ASAP] Discovery of Macrocyclic Peptide Binders, Covalent Modifiers, and Degraders of a Structured RNA by mRNA Display
by Xiyuan Yao, Kanokpol Aphicho, Shubhashree Pani, Anuchit Rupanya, Tong Lan, and Bryan C. Dickinson
Journal of the American Chemical Society
DOI: 10.1021/jacs.5c05540
Patrick Zanon likes this
16 Sep 14:16
A Condensate Dissolver
I’ve written several times over the last few years about biomolecular condensates, also known as “membraneless organelles” and (confusingly) by several other names. Whatever you call them, these are phase-separated droplets that form reversibly under various cellular conditions, and they often consist of mixtures of proteins and RNA species. There are particular protein sequences and charge distributions that are more common among condensate-formers, and disordered proteins are over-represented as well, but there’s a lot of variety in composition, lifetime, and localization.
I was invited to a meeting on these topics back in 2018 and found the field very interesting. It seemed obvious that these things were performing important cellular functions and that they had been largely overlooked. Well, except by microscopists, who had given them names like “speckles”, “granules”, “bodies” and so on. It was quite a while before their common features were recognized. Not long after that meeting several condensate-focused startups launched, not all of which are still with us. I spent a good amount of time digesting the research in the field, as much as it was actually digestible, and trying to come up with a good actionable application to drug discovery.
But I was unable to. No matter how I came at it, the whole field seemed to still be in too early a state for these opportunities. Indeed, my impression of some of the startups was that they set about trying to bring some order to things to see what they had and what might present the best opportunities, and I suspect that process is still continuing. A few things did stand out: everyone was agreed that proteins like TDP43 and FUS formed stress-granule condensates, and that these seemed to somehow go haywire in some neurodegenerative disorders. The simplest way to look at it was that the condensates didn’t seem to dissolve on cue once the cellular stress was removed, but rather hung around, aging from liquid droplets to something more like gelatinous blobs and eventually to outright solid deposits that were associated with pathological states in neurons. That might be too simple a way to look at it - nothing in neurodegeneration is ever as simple as it looks, from what I’ve seen - but it’s not a bad place to start. And a lot of people have indeed been starting right there.
This recent paper makes the case that interfering with that “condensate aging” process might be beneficial, as hoped, and the authors searched for small molecules that could induce this phenotypic outcome. There had been some condensate-dissolving molecules identified over the years, but they tended to be like the prototype of that group, 1,6-hexanediol. That one really does seem to dissolve condensates, but probably in the same way that it might make a useful additive to a spray for cleaning shower doors: in some ways it’s just a solvent. And as you’d figure, it has a lot of other effects on cells, making it a pretty poor tool for assays and outright hopeless as a potential mode of treatment.
This new paper settled on lipoamide. That makes some chemical sense as a hit - the formation and dissolution of stress granules seems to involve redox changes in some key proteins, and the disulfide group in lipoamide might be expected to get into the middle of that chemistry. The paper shows that various cell lines expressing fluorescently tagged versions of stress granule proteins (such as FUS and TDP43) are sensitive to lipoamide treatment, acutely or with pretreatment before the induced formation of the granules as a preventative. Interestingly, and array of other known condensates in both the cytoplasm and nucleus were unaffected. Even the source of stress granule formation mattered: granule formation on exposure to arsenate, oxidative stress, or osmotic shock was inhibited, while formation after heat treatment or inhibition of glycolosis went on apparently as before. There are stress granules and there are stress granules, it seems.
Nitrogen-isotope-labeled versions of lipoamide or a derivative of it with a photoreactive diazirine group both showed that it partitions well into cells, and that it also gets concentrated in the stress granules (as well as other organelles). SAR exploration around the structure showed that the lipoamide stereochemistry didn’t seem to matter, indicating that it’s probably not a specific protein-binding event that’s in play. And the activity around the amide group was rather flat - some a bit better, some a bit worse. In fact, the entire carboxamide could be deleted without completely losing activity. But the disulfide (the dithiolane ring) was crucial. Six- and seven-membered disulfides were actually inactive (the size of such rings is known to affect the redox potential).
Proteomic work showed that disordered protein regions with lots of arginine and tyrosine residues interacted with lipoamide. FUS itself does not, but two other proteins that are known to localize to stress granules do, SFPQ and SRSF1. Their own sequence oddities are found in their names, which are acronyms for “splicing factor proline- and glutamine-rich” and “serine-arginine rich splicing factor 1”. Knocking out the former impaired the ability of lipoamide to keep stress granules from forming, and knocking out the latter stops it from working at all.
After this came the real test in cells. Lipoamide does actually seem to rescue the functions of FUS and TDP43, presumably by allowing them to be either released from stress granules or by preventing their formation outright, and it actually seems to alleviate the ALS phenotypes in relevant models with both human- and animal-derived cells expressing mutant forms FUS and TDP43. On top of that, it also showed beneficial effects in small-animal model systems in C. elegans and Drosophila. That’s really interesting, but it also raises a lot of questions about the formation of those stress granules and their role in normal cells. The granules in those mutant cells aren’t really associated with oxidative stress, for example, and you also have to wonder about the consequences for normal cells if they are indeed unable to form stress granules after treatment with lipoamide or something like it. They’re presumably there for a reason! And more work will be needed to show a solid link between stress granule dissolution and these phenotypic improvements. But now it looks like there are some good tools with which to get started on that, which is a real improvement.
16 Sep 14:00
Tumour-specific STING agonist synthesis via a two-component prodrug system
by Nai-Shu Hsu
Nature Chemistry, Published online: 16 September 2025; doi:10.1038/s41557-025-01930-9
STING is a promising drug target, but selective activation is necessary for safety and efficacy. Researchers have developed a two-component prodrug system for potent pharmacological activation of STING that offers excellent tumour targeting.
16 Sep 13:58
Design, Synthesis, and Biological Evaluation of Lipid-Modified Derivatives of Tunicamycins
by Kazuki Yamamoto
Chemistry. 2025 Sep 15:e02296. doi: 10.1002/chem.202502296. Online ahead of print.
ABSTRACT
Naturally occurring antibiotic tunicamycin targets bacterial peptidoglycan biosynthesis by inhibiting bacterial phospho-N-acetylmuraminic acid (MurNAc)-pentapeptide translocase (MraY), but it also inhibits human UDP-N-acetylglucosamine (GlcNAc): polyprenol phosphate translocase (GPT), leading to cytotoxicity. This study thoroughly investigated the structure-activity relationship of the fatty acyl side chain of tunicamycin to develop MraY-selective inhibitors, based on structural differences between MraY and GPT. Longer alkyl chains and flexible structures were found to favor MraY inhibitory activity, and benzene rings were acceptable for binding. The hybrid analogue containing oleoyl group, which contributed most significantly to MraY inhibitory activity, and the MurNAc moiety, which is important for MraY-selective inhibition, showed enhanced MraY inhibitory activity as well as improved antibacterial activity against S. aureus and E. faecium.
PMID:40952100 | DOI:10.1002/chem.202502296
14 Sep 00:43
[ASAP] Metabolic Tagging Reveals Surface-Associated Lipoproteins in Mycobacteria
by Lia A. Parkin, Kindra L. Becker, Julian P. Maceren, Aseem Palande, Neetika Jaisinghani, Mary L. Previti, and Jessica C. Seeliger
ACS Infectious Diseases
DOI: 10.1021/acsinfecdis.5c00365
14 Sep 00:38
[ASAP] Immunoglobulin-Directed Phase Separation for Cell-Specific Modulation of Receptor Signaling
by Weishuai Ren, Peiyuan Zheng, Ziting Zhou, Min Zhou, Mengling Wu, Yanchao Ding, Haolin Jiang, Pilong Li, and Juanjuan Du
Karl Ociuscondensates
Journal of the American Chemical Society
DOI: 10.1021/jacs.5c09699
14 Sep 00:36
[ASAP] Cysteine Reactivity Profiling Illuminates Monoclonal Antibody Disulfide Bond Reduction Mechanisms in Biopharmaceutical Process Intermediates
by Taku Tsukidate, Zhenshu Wang, Andrew Hsieh, Patricia Rose, and Xuanwen Li
Journal of the American Society for Mass Spectrometry
DOI: 10.1021/jasms.5c00204
12 Sep 21:25
[ASAP] A Next-Generation Brain-Targeting Peptide: KS-487 Rivals Angiopep-2 in BBB Penetration with Enhanced Selectivity
by Kensuke Asukabe, Nagi Yamashita, Runa Fujimoto, Kotaro Sakamoto, and Eijiro Miyako
Karl Ociusin the BBB ??
Bioconjugate Chemistry
DOI: 10.1021/acs.bioconjchem.5c00352
12 Sep 21:23
[ASAP] Development of Cyclooctyne-Nitrone Based Click Release Chemistry for Bioorthogonal Prodrug Activation both In Vitro and In Vivo
by Xiaowei Xu, Yuanan Wang, Yangfei Shi, Xin Wang, Xidan Tong, Yanzhao Chen, Yan Zhao, Jiaxuan Chen, Weiwei Guo, and Yueqin Zheng
Journal of the American Chemical Society
DOI: 10.1021/jacs.5c08152
liuyufengno1 likes this
12 Sep 21:21
[ASAP] Enzyme-Activated Sugar-Coated Bifunctional Degraders
by Qian Zhu, Gerhard Fischer, Steven S. Cheng, N. Connor Payne, Daniel Peter, Alison C. Mody, Silvia Arce-Solano, Dacheng Shen, Zhi Lin, Ralph Mazitschek, Dirk Kessler, and Christina M. Woo
Journal of the American Chemical Society
DOI: 10.1021/jacs.5c09843
Tim C likes this
11 Sep 13:06
Real-time imaging of protein microenvironment changes in cells with rotor-based fluorescent amino acids
by Shudan Yang
Nature Chemical Biology, Published online: 11 September 2025; doi:10.1038/s41589-025-02003-1
The use of bulky protein tags and the limited positions available for probe introduction restrict current methods for studying protein microenvironments at high spatial resolution. Here the authors genetically incorporate small environment-sensitive fluorescent amino acids to visualize real-time microenvironmental changes at specific protein substructures.
09 Sep 18:55
Divergent cytokine and transcriptional signatures control functional T follicular helper cell heterogeneity
by Lennard Dalit
Karl OciusPesticides
Nature Immunology, Published online: 09 September 2025; doi:10.1038/s41590-025-02258-9
Dalit, Tan and colleagues provide a multiomic profile of T follicular helper (TFH) cells responses to diverse pathogens, revealing a blueprint for transcriptional flexibility and new tools to interrogate TFH heterogeneity in mice and humans.
09 Sep 18:47
[ASAP] “Cut-and-Sew” Reactions of β-Lactams via C–C Bond Activation
by Liyan Kan, Rui Zhang, Shou-Lin Lu, Yash Hari, and Guangbin Dong
Journal of the American Chemical Society
DOI: 10.1021/jacs.5c12770
Seb likes this
09 Sep 18:45
Navigating condensate micropolarity to enhance small-molecule drug targeting
by Jian Ouyang
Karl Ociuscondensates
Nature Chemical Biology, Published online: 09 September 2025; doi:10.1038/s41589-025-02017-9
Using computational and experimental methods, Ouyang and Chen et al. reveal a drug design principle that the hydrophobic properties of small-molecule drugs significantly influence their ability to engage with and effectively target phase-separated proteins.
07 Sep 22:13
1,2-naphthoquinone enhances IFN-gamma-induced MHC-I expression in dendritic cells, thereby inducing CD8 T cell activation
by Kazuyuki Furuta
Karl Ociusthe molecule by itself does not work
Biochem Biophys Res Commun. 2025 Sep 12;779:152453. doi: 10.1016/j.bbrc.2025.152453. Epub 2025 Aug 6.
ABSTRACT
Dendritic cells play a crucial role in immune responses by capturing pathogens and presenting antigens to T cells via major histocompatibility complex (MHC) molecules, thus triggering adaptive immune responses. 1,2-naphthoquinone (1,2-NQ), a quinone found in diesel exhaust and cigarette smoke, has various physiological functions. In this study, we investigated the effect of 1,2-NQ on the expression of antigen presentation-related molecules in the dendritic cell line DC2.4. The results revealed that 1,2-NQ enhanced the IFN-γ-induced upregulation of MHC-I expression at the transcriptional level. Moreover, it upregulated the expression of NLRC5, a transcriptional activator of MHC-I. 1,2-NQ is a reactive oxygen species (ROS) producing reagent. The 1,2-NQ-induced upregulation of MHC-I expression and downregulation of MHC-II expression were abolished by the ROS scavenger N-acetylcysteine. Similar effects on MHC expression were also observed with ROS-inducing reagents, such as paraquat and diethyl maleate. In addition, dendritic cells stimulated with 1,2-NQ exhibited enhanced efficacy in CD8 T cell activation, which was accompanied by increased IFN-γ production by T cells. These findings demonstrate that 1,2-NQ enhances the IFN-γ-induced activation of dendritic cells and promotes the activation of CD8 T cells.
PMID:40779979 | DOI:10.1016/j.bbrc.2025.152453
04 Sep 17:30
[ASAP] Time-Resolved Analysis of Protein–Protein Ensembles Using a Destabilizing Domain to Map Dynamic Interactions of SARS-CoV-2 nsp15
by Crissey Cameron, R. Mason Clark, Adam M. Metts, Runze M. Jiang, Toya D. Scaggs, Kwangho Kim, Gary A. Sulikowski, and Lars Plate
Karl OciusCAA
ACS Chemical Biology
DOI: 10.1021/acschembio.5c00377
04 Sep 17:28
[ASAP] Temporal and Spatial Characterization of CUL3KLHL20-Driven Targeted Degradation of BET Family BRD Proteins by the Macrocycle-Based Degrader BTR2004
by Phoebe H. Fechtmeyer, Cameron Martinez, and Johannes T.-H. Yeh
ACS Chemical Biology
DOI: 10.1021/acschembio.5c00343
03 Sep 16:45
Metabolic rewiring of isoniazid sensitivity in Mycobacterium tuberculosis
by Erin R Wang
Proc Natl Acad Sci U S A. 2025 Sep 9;122(36):e2421336122. doi: 10.1073/pnas.2421336122. Epub 2025 Sep 2.
ABSTRACT
Isoniazid (INH) inhibits mycolic acid synthesis in Mycobacterium tuberculosis (Mtb) and is a cornerstone of treatment regimens against this deadly pathogen. However, over 10% of Mtb infections are INH-resistant. The compound C10 can sensitize clinically relevant INH-resistant mutants to killing by INH. Thus, understanding the mechanism of action for C10 could aid in designing new strategies for circumventing drug resistance. We find that C10 treatment reroutes carbon flux toward valine, drawing carbon away from gluconeogenesis and the TCA cycle. As a result, C10 decreases cell envelope capsule thickness and blocks an accumulation of peptidoglycan precursors that occurs in response to INH treatment in an INH-resistant Mtb katG mutant. In this altered metabolic state induced by C10, INH treatment of the INH-resistant Mtb katG mutant inhibits peptidoglycan synthesis, precipitating collapse of cell envelope integrity. Pyruvate supplementation relieves the C10-induced requirement for carbon flux toward valine, enhancing carbon assimilation into cell envelope precursors and restoring resistance to INH. In addition, we identify the formation of isoniazid-pyruvate in INH-treated katGW328L Mtb, where pyruvate sequesters INH, lowering the concentration of INH available to inhibit Mtb. Together, our findings reveal a bactericidal activity for INH in Mtb that can function in INH-resistant mutants independently of INH-mediated inhibition of mycolic acid synthesis. This activity for INH can be elicited by shifting carbon flux toward valine and away from cell envelope precursor synthesis, highlighting a metabolic vulnerability that can be exploited to kill INH-resistant Mtb.
PMID:40892921 | PMC:PMC12435213 | DOI:10.1073/pnas.2421336122
03 Sep 14:08
[ASAP] Overcoming Immune Checkpoint Inhibitor Resistance with Potent, Selective Dual αvβ6/8 Inhibitors Based on Engineered Lasso Peptides
by Anna Lechner, Peter A. Jordan, Gabriella Costa Machado da Cruz, Jacob Lamson, Jessica Gordon, Bethany K. Okada, Kelsey Anderson, Rajan Chaudhari, Christopher J. Rosario, Jasmine Mikesell, Scott A. McPhee, and Mark J. Burk
Journal of the American Chemical Society
DOI: 10.1021/jacs.5c06142
03 Sep 14:02
A label-free method for measuring the composition of multicomponent biomolecular condensates
by Patrick M. McCall
Karl Ociusthe impact of labels on condensates
Nature Chemistry, Published online: 03 September 2025; doi:10.1038/s41557-025-01928-3
Biomolecular condensates are made of multiple components but current techniques cannot capture their complex composition quantitatively. Now it has been shown that the dense-phase binodal point defining the composition of multicomponent condensates can be inferred precisely from the intersection of a spectrometrically determined tie-line with an isorefractive line obtained from quantitative phase imaging.
03 Sep 14:00
Reply to: Mass spectrometry and enzyme assays refute histone tyrosine sulfation
by Xue Bai
Karl Ociusrebuttal to our seminar speaker
Nature Chemical Biology, Published online: 01 September 2025; doi:10.1038/s41589-025-01995-0
Reply to: Mass spectrometry and enzyme assays refute histone tyrosine sulfation
03 Sep 13:52
Metabolic rewiring of isoniazid sensitivity in Mycobacterium tuberculosis
by Erin R Wang
Proc Natl Acad Sci U S A. 2025 Sep 9;122(36):e2421336122. doi: 10.1073/pnas.2421336122. Epub 2025 Sep 2.
ABSTRACT
Isoniazid (INH) inhibits mycolic acid synthesis in Mycobacterium tuberculosis (Mtb) and is a cornerstone of treatment regimens against this deadly pathogen. However, over 10% of Mtb infections are INH-resistant. The compound C10 can sensitize clinically relevant INH-resistant mutants to killing by INH. Thus, understanding the mechanism of action for C10 could aid in designing new strategies for circumventing drug resistance. We find that C10 treatment reroutes carbon flux toward valine, drawing carbon away from gluconeogenesis and the TCA cycle. As a result, C10 decreases cell envelope capsule thickness and blocks an accumulation of peptidoglycan precursors that occurs in response to INH treatment in an INH-resistant Mtb katG mutant. In this altered metabolic state induced by C10, INH treatment of the INH-resistant Mtb katG mutant inhibits peptidoglycan synthesis, precipitating collapse of cell envelope integrity. Pyruvate supplementation relieves the C10-induced requirement for carbon flux toward valine, enhancing carbon assimilation into cell envelope precursors and restoring resistance to INH. In addition, we identify the formation of isoniazid-pyruvate in INH-treated katGW328L Mtb, where pyruvate sequesters INH, lowering the concentration of INH available to inhibit Mtb. Together, our findings reveal a bactericidal activity for INH in Mtb that can function in INH-resistant mutants independently of INH-mediated inhibition of mycolic acid synthesis. This activity for INH can be elicited by shifting carbon flux toward valine and away from cell envelope precursor synthesis, highlighting a metabolic vulnerability that can be exploited to kill INH-resistant Mtb.
PMID:40892921 | DOI:10.1073/pnas.2421336122