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Structural engineering of antimicrobials for optimal broad-spectrum activity

Green Chemical Engineering 2024年第4期5卷 473-482页

作者： Arunmozhiarasi Armugam Diane S.W.Lim Siti Nurhanna Riduan Shook Pui Chan Jerome Asugan Yugen Zhang Institute of Bioengineering and Bioimaging 31 Biopolis WayThe Nanos#07-01138669Singapore Institute of Sustainability for Chemicals Energy and Environment(ISCE2)Agency for ScienceTechnology and Research(A^(*)STAR)1 Pesek Road Jurong Island627833Singapore Diploma in Biomedical Science School of Chemical and Life SciencesSingapore Polytechnic500 Dover Road139651Singapore

Antimicrobial materials are a crucial component in eradicating and managing the spread of infectious *** are expected to act on a broad-spectrum of microbes,including emerging pathogens which could cause the next Disease ***,we reassessed a series of antimicrobial imidazolium polymers on our shelves and uncovered extended functionality through dual modes of *** redesigning their structures,a truly broadspectrum antimicrobial material with optimized activity against bacteria(G+ve,G-ve)and fungi,as well as enveloped and non-enveloped viruses was *** demonstrated that the imidazolium polymer exhibits dual modes of function against microbes:targeting the microbial membrane and binding *** latter DNA binding affinity was found to be key against non-enveloped *** this insight,we designed small molecule compounds that exhibited optimum broad-spectrum antimicrobial activity and excellent efficacy against ESKAPE group of pathogens that are responsible for some of the deadliest nosocomial infections *** results could also shed light on the design of broad-spectrum antimicrobial compounds against Disease X.

关键词： Broad-spectrum Antimicrobial Polyimidazolium structure-function Membrane active

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functional Complexity on a Cellular Scale: Why In Situ Analyses Are Indispensable for Our Understanding of Lignified Tissues

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JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024年第24期72卷 13552-13560页

作者： Blaschek, Leonard Serk, Henrik Pesquet, Edouard Univ Copenhagen Copenhagen Plant Sci Ctr CPSC Dept Plant & Environm Sci DK-1871 Frederiksberg Denmark Umea Univ Umea Plant Sci Ctr UPSC Dept Plant Physiol S-90736 Umea Sweden Stockholm Univ Dept Ecol Environm & Plant Sci DEEP S-10691 Stockholm Sweden

Lignins are a key adaptation that enables vascular plants to thrive in terrestrial habitats. Lignin is heterogeneous, containing upward of 30 different monomers, and its function is multifarious: It provides structural support, predetermined breaking points, ultraviolet protection, diffusion barriers, pathogen resistance, and drought resilience. Recent studies, carefully characterizing lignin in situ, have started to identify specific lignin compositions and ultrastructures with distinct cellular functions, but our understanding remains fractional. We summarize recent works and highlight where further in situ lignin analysis could provide valuable insights into plant growth and adaptation. We also summarize strengths and weaknesses of lignin in situ analysis methods.

关键词： lignin in situ quantification cell wall structure-function lignin evolution chemical imaging

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GO/HTPB composite liner for anti-migration of small molecules

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Defence Technology（防务技术） 2023年第4期22卷 156-165页

作者： Hao Li Jie Wei Ya-nan Zhang Yu-bing Hu Wei Jiang Teng-yue Zhang College of Materials Science and Engineering Nanjing Tech UniversityNanjing211816China National Special Superfine Powder Engineering Research Center of China Nanjing University of Science and TechnologyNanjing210014China Key Laboratory of Special Energy Materials Nanjing University of Science and TechnologyMinistry of EducationNanjing210094China China Research and Development Academy of Machinery Equipment Beijing100089China

Hydroxyl-terminated polybutadiene/toluene diisocyanate(HTPB/TDI)system is widely used in composite solid *** migrations of plasticizers and water molecules from solid propellants and surrounding environment to the inhibitor have always been the important *** study focuses on the preparation,characterization and anti-migration behavior of graphene oxide(GO)/HTPB nanocomposite *** GO/HTPB(GH)composite liners affect the migration of small molecules through a tighter cross-linked structure and weakening function of small molecule *** anti-migration performance of the liner at different temperatures was analyzed,and the influence of the added amount of GO on the anti-migration performance and adhesion performance was also systematically *** overall performance of the liner is optimized when the amount of GO filler is 0.3 wt%.After adding 0.3 wt%GO,the concentration of dioctyl sebacate(DOS)migrated into the liner is decreased by 23.28%,and the concentration of water molecules is decreased by 51.89%,indicating that the introduction of GO can significantly improve the anti-migration performance of the *** addition,the bond strength is greatly increased from 0.25 MPa to 0.95 MPa,which meets the application requirements of the current propellant *** research provides an important way for the preparation of structure-function synergistic anti-migration composite liners.

关键词： Graphene oxide Liner structure-function Anti-migration Bonding

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structure-activity relationship of isoprenoid triazole bisphosphonatebased geranylgeranyl diphosphate synthase inhibitors: Effects on pharmacokinetics, biodistribution, and hepatic transporters

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DRUG METABOLISM AND DISPOSITION 2025年第3期53卷 100038页

作者： Haney, Staci L. Chhonker, Yashpal S. Rashid, Mamunur Murry, Daryl J. Holstein, Sarah A. Univ Nebraska Med Ctr Dept Internal Med Omaha NE 68198 USA Univ Nebraska Med Ctr Dept Pharm Practice & Sci Omaha NE 68198 USA

Geranylgeranyl diphosphate synthase produces the isoprenoid geranylgeranyl diphosphate, which is used in protein geranylgeranylation. Our previous work illustrates that geranylgeranyl diphosphate synthase inhibitors (GGSIs) disrupt Rab-mediated protein trafficking in cells, inducing the unfolded protein response pathway and apoptosis. structure-function studies of our GGSIs, which are isoprenoid triazole bisphosphonates, have revealed a complex relationship between GGSI structure and enzymatic, cellular, and in vivo activities. The dose-limiting toxicity of this family of GGSIs is hepatic, and the mechanisms underlying their hepatic uptake are unexplored. Here, we evaluate the pharmacokinetics (PK) and biodistribution of a pair of potent GGSIs that are olefin isomers (homogeranyl [HG] and homoneryl [HN]). We investigate whether these isomers, as well as their a-methylated analogs (HG-me and HN-me), are substrates for key hepatic transporters and explore the effects of these GGSIs on the expression of a panel of hepatic transporters and cytochrome P450s. The PK/biodistribution studies revealed that both systemic exposure and liver levels of HG were significantly higher than that of HN across multiple time points. Conversely, HN was present at 4-fold higher concentrations in the bile at 2 hours postinjection relative to HG. HG-me and HN-me, but not HG or HN, were determined to be substrates of hepatic transport proteins OATP1B1 and OATP1B3. While the hepatic expression of several transporters and cytochrome P450 were altered by GGSI treatment, no significant differences in expression patterns between pairs of olefin isomers were observed. Collectively, these studies reveal that GGSI structure, including olefin stereochemistry, impacts PK profile, biodistribution, and hepatic transporter affinity. Significance Statement: Our understanding of the in vivo structure-activity relationship of our novel geranylgeranyl diphosphate synthase inhibitors has expanded, demonstrati

关键词： Geranylgeranyl diphosphate synthase Hepatic uptake structure-function

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Mapping the structural heterogeneity of Pup ligase PafA using H/D exchange mass spectrometry

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JOURNAL OF BIOLOGICAL CHEMISTRY 2025年第5期301卷 108437页

作者： Plourde, Alicia Ogata-Bean, Jacquelyn C. Vahidi, Siavash Univ Guelph Dept Mol & Cellular Biol Guelph ON Canada

The Pup-proteasome system (PPS) is a unique bacterial proteolytic pathway found in some bacterial species, including in Mycobacterium tuberculosis, that plays a vital role in maintaining proteome integrity and survival during infection. Pupylation is the process of tagging substrates with Pup for degradation and is catalyzed by PafA, the sole Pup ligase in bacteria. However, how PafA interacts with diverse targets and its oligomeric state remains poorly understood. Although X-ray crystal structures have characterized PafA as a domain-swapped dimer, it is widely regarded as functionally active in its monomeric form. It remains to be established whether PafA dimerizes in solution, and how dimerization influences its function. In this study, we employed hydrogen-deuterium exchange mass spectrometry (HDX-MS) alongside complementary biophysical techniques to explore the oligomeric states and conformational dynamics of PafA. We show that recombinantly-produced PafA exists in a monomeric and a domain-swapped dimeric state in solution. Although nucleotide binding stabilizes PafAdimer, it primarily adopts a catalytically inactive conformation. Our HDX-MS highlighted regions throughout the N- and C-terminal domains that facilitate the PafA dimerization process. HDX-MS also revealed nucleotide binding induces global conformational changes on PafAmonomer, underscoring the structural plasticity of this promiscuous enzyme. Our findings enhance our understanding of the structural and conformational heterogeneity of PafA and demonstrate how nucleotide binding and dimerization may influence its function.

关键词： enzyme structure hydrogen exchange mass spectrometry protein conformation proteostasis pupylation structure-function Pup-proteasome system

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Associations Between Contrast Sensitivity, Optical Coherence Tomography Features and Progression From Intermediate to Late Age-related Macular Degeneration

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AMERICAN JOURNAL OF OPHTHALMOLOGY 2025年 271卷 175-187页

作者： Bennett, Cade Romano, Francesco Vingopoulos, Filippos Garcia, Mauricio Ding, Xinyi Bannerman, Augustine Ploumi, Ioanna Ntentakis, Dimitrios Stettler, Isabella Overbey, Katherine Baldwin, Grace Bejjani, Romy Garg, Itika Rodriguez, Jocelyn Lains, Ines Kim, Leo A. Vavvas, Demetrios Husain, Deeba Miller, Joan W. Miller, John B. Harvard Med Sch Massachusetts Eye & Ear Harvard Retinal Imaging Lab Boston MA USA Massachusetts Eye & Ear Dept Ophthalmol Retina Serv Boston MA USA Stanford Univ Byers Eye Inst Sch Med Dept Ophthalmol Palo Alto CA USA

center dot PURPOSE: Establishing associations between structure, function, and clinical outcomes in intermediate age- related macular degeneration (iAMD) remains an unmet need. This study aims to (1) cross-sectionally investigate the relationships between optical coherence tomography (OCT) biomarkers and quantitative contrast sensitivity function (qCSF)-measured contrast sensitivity (CS), and (2) longitudinally assess their relationship with progression from iAMD to late stages of the disease. center dot DESIGN: Cross-sectional and cohort study. center dot METHODS: Our study was conducted at Massachusetts Eye and Ear (Boston, MA, USA) and included eyes with (1) baseline diagnosis of iAMD, (2) same-day OCT and qCSF test, (3) visual acuity >= 20/200 Snellen, and (4) 24 + months of follow-up. qCSF metrics included the area under the logCSF curve, contrast acuity, and CS thresholds at 1- to 18-cycle-per-degree (cpd). Two independent graders reviewed macular OCT scans for various biomarkers, and outer nuclear layer (ONL) thickness and retinal pigment epithelium (RPE) volume were measured. Progression to wet AMD or geographic atrophy (GA) was confirmed using imaging studies. Generalized linear mixed-effects models assessed associations between qCSF and OCT biomarkers, while Cox regression models evaluated their association with progression to late AMD. center dot RESULTS: We included 205 iAMD eyes from 134 patients (age: 73 [69-78] years;63% female). Higher RPE volume in the central subfield and a greater number of intraretinal hyperreflective foci were associated with reduced area under the logCSF curve, contrast acuity, and CS at 6 to 12 cpd ( P < .05). ONL thinning in the inner ring and a greater number of intraretinal hyperreflective foci were associated with reduced CS at 1 and 3 cpd ( P < .05). During follow-up, 35 eyes developed wet AMD (17%) and 53 progressed to GA (26%). subretinal drusenoid deposit, ONL thinning in the inner ring, and reduced CS at 1.5 cpd were

关键词： OCT biomarkers contrast sensitivity function iAMD intermediate AMD progression qCSF structure-function

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Structural and functional analysis of Pseudomonas aeruginosa PelA provides insight into the modification of the Pel exopolysaccharide

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JOURNAL OF BIOLOGICAL CHEMISTRY 2025年第5期301卷 108432页

作者： Van Loon, Jaime C. Le Mauff, Francois Vargas, Mario A. Gilbert, Stephanie Pfoh, Roland Morrison, Zachary A. Razvi, Erum Nitz, Mark Sheppard, Donald C. Howell, P. Lynne Hosp Sick Children Program Mol Med Toronto ON Canada Univ Toronto Dept Biochem Toronto ON Canada McGill Univ Fac Med Dept Microbiol & Immunol Montreal PQ Canada McGill Univ Infect Dis & Immun Global Hlth Res Inst Hlth Ctr Montreal PQ Canada McGill Interdisciplinary Initiat Infect & Immun Montreal PQ Canada Glyco NET Integrated Serv Microbial Glyc Node Montreal PQ Canada Univ Toronto Dept Chem Toronto ON Canada

A major biofilm matrix determinant of Pseudomonas aeruginosa is the partially deacetylated a-1,4 linked N-acetylgalactosamine polymer, Pel. After synthesis and transport of the GalNAc polysaccharide across the inner membrane, PelA partially deacetylates and hydrolyzes Pel before its export out of the cell via PelB. While the Pel modification and export proteins are known to interact in the periplasm, it is unclear how the interaction of PelA and PelB coordinates these processes. To determine how PelA modifies the polymer, we determined its structure to 2.1 & Aring;and found a unique arrangement of four distinct domains. We have shown previously that the hydrolase domain exhibits endo-a-1,4-N-acetylgalactosaminidase activity. Characterization of the deacetylase domain revealed that PelA is the founding member of a new carbohydrate esterase family, CE21. Further, we found that the PelAB interaction enhances the deacetylation of Nacetylgalactosamine oligosaccharides. Using the PelA structure in conjunction with AlphaFold2 modeling of the PelAB complex, we propose a model wherein PelB guides Pel to the deacetylase domain of PelA and subsequently to the porin domain of PelB for export. Perturbation or loss of the PelAB interaction would result in less efficient deacetylation and potentially increased Pel hydrolysis. In PelA homologs across many phyla, the predicted structure and active sites are conserved, suggesting a common modification mechanism in Gram-negative bacterial species containing a functional pel operon.

关键词： biofilm pel polysaccharide crystallography structure-function

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Tendon-targeted knockout of collagen XI disrupts patellar and Achilles tendon structure and mechanical properties during murine postnatal development

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CONNECTIVE TISSUE RESEARCH 2024年第6期65卷 497-510页

作者： Cohen, Jordan S. Fung, Ashley K. Stein, Matthew K. Darrieutort-Laffite, Christelle Weiss, Stephanie N. Shetye, Snehal S. Thurlow, Nat A. Nuss, Courtney A. Dyment, Nathaniel A. Soslowsky, Louis J. Univ Penn Dept Orthopaed Surg McKay Orthopaed Res Lab Philadelphia PA USA Nantes Univ INSERM Regenerat Med & Skeleton RMeSUMR 1229OnirisCHU Nantes Nantes France

Background: Collagen XI is a fibril-forming collagen typically associated with type II collagen tissues but is also expressed in type I collagen-rich tendons, especially during development. We previously showed that tendon-targeted (Scx-Cre) Col11a1 knockout mice have smaller tendons in adulthood with aberrant fibril structure and impaired mechanical properties. However, the manifestation of this phenotype is not clearly understood. Therefore, our objective is to define the spatiotemporal roles of collagen XI in tendon structure-function during postnatal development. Given the high expression of collagen XI during embryonic development, we hypothesized that collagen XI knockout leads to the deposition of weakened extracellular matrix during early postnatal timepoints, disrupting the establishment of tendon structure and function. Methods: Patellar and Achilles tendons from postnatal (P) days 0, 10, 20, and 30 tendon-targeted scleraxis-Cre heterozygous and homozygous Col11a1 knockout mice were evaluated for morphology, nuclear organization, fibril morphology, mechanical properties, and gene expression. Results: At P0, there were no differences in tendon length or fibril diameter of either tendon. By P10, striking structural and functional differences emerged, with collagen XI deficiency resulting in increased tendon length, a heterogeneous and larger diameter population of fibrils, and inferior mechanical properties in both patellar and Achilles tendons. Differences increased in magnitude through P30, supporting our hypothesis that impaired structure-function during postnatal development may drive tendon lengthening and reduced mechanical properties. Conclusions: Though collagen XI is a quantitatively minor component of the tendon extracellular matrix, these results highlight the critical role of collagen XI in the acquisition of tendon structure-function.

关键词： Tendon collagen XI postnatal development structure-function

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Exploration of structural differences between dairy and plant-based cheese

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FOOD structure-NETHERLANDS 2025年 44卷

作者： Dobson, S. Marangoni, A. G. Univ Guelph Dept Food Sci 50 Stone Rd E Guelph ON N1G 2W1 Canada

The functionality and microstructure of commercial dairy cheese, commercial plant-based cheese, and highprotein plant-based cheese (HPC) were analyzed to explore the structure-function relationship. Commercial dairy cheese exhibited the best functionality, showcasing an ideal texture profile alongside optimal melting and stretch characteristics. In contrast, commercial plant-based cheese showed the least resemblance to dairy cheese, with the lowest melting and stretching properties, as well as considerable structural integrity after heating, marked by the highest G' and lowest tan delta values. HPC demonstrated notable improvements in textural properties compared to commercial plant-based cheese, indicated by enhanced melting and stretching, lower G', and higher tan delta, reflecting its viscous nature. The microstructural analysis on cold samples revealed that both dairy and commercial plant-based cheeses contained a high density of small fat globules, while HPC had significantly larger globules and protein aggregates. Upon melting, dairy cheese and HPC displayed similar microstructures, characterized by fat pooling and a yielding continuous matrix, correlating with their melting and stretching abilities. In contrast, the melted commercial plant-based cheese exhibited minimal structural changes from its cold state, indicating that its starch matrix was irreversible and did not yield under heat. Ultimately, to achieve melting and stretching in both dairy and plant-based cheeses, the network must yield upon heating, allowing for fat pooling but maintaining connectivity of the continuous matrix.

关键词： High protein plant-based cheese Dairy cheese Microstructure structure-function

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Characterization of lignin-degrading enzyme PmdC, which catalyzes a key step in the synthesis of polymer precursor 2-pyrone-4,6-dicarboxylic acid

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JOURNAL OF BIOLOGICAL CHEMISTRY 2024年第10期300卷 107736-107736页

作者： Rodrigues, Andria V. Moriarty, Nigel W. Kakumanu, Ramu DeGiovanni, Andy Pereira, Jose Henrique Gin, Jennifer W. Chen, Yan Baidoo, Edward E. K. Petzold, Christopher J. Adams, Paul D. Joint BioEnergy Inst Emeryville CA 94608 USA Lawrence Berkeley Natl Lab Mol Biophys & Integrated Bioimaging Berkeley CA 94720 USA Lawrence Berkeley Natl Lab Biol Syst & Engn Div Berkeley CA USA Dept Energy Agile BioFoundry Emeryville CA USA Univ Calif Berkeley Dept Bioengn Berkeley CA 94720 USA

Pyrone-2,4-dicarboxylic acid (PDC) is a valuable polymer precursor that can be derived from the microbial degradation of lignin. The key enzyme in the microbial production of PDC is 4-carboxy-2-hydroxymuconate-6-semialdehyde (CHMS) dehydrogenase, which acts on the substrate CHMS. We present the crystal structure of CHMS dehydrogenase (PmdC from Comamonas testosteroni) bound to the cofactor NADP, shedding light on its three-dimensional architecture, and revealing residues responsible for binding NADP. Using a combination of structural homology, molecular docking, and quantum chemistry calculations, we have predicted the binding site of CHMS. Key histidine residues in a conserved sequence are identified as crucial for binding the hydroxyl group of CHMS and facilitating dehydrogenation with NADP. Mutating these histidine residues results in a loss of enzyme activity, leading to a proposed model for the enzyme's mechanism. These findings are expected to help guide efforts in protein and metabolic engineering to enhance PDC yields in biological routes to polymer feedstock synthesis.

关键词： NADP oxidoreductase lignin degradation polymer synthesis pyrone 2 4 dicarboxylic acid enzyme catalysis structure-function crystal structure alphafold ligand docking computational modeling

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