ACS Central SciencePub Date : 2025-02-03DOI: 10.1021/acscentsci.5c0001810.1021/acscentsci.5c00018
Mark A. B. Kreutzberger, Le Tracy Yu, Thi H. Bui, Maria C. Hancu, Michael D. Purdy, Tomasz Osinski, Peter M. Kasson, Edward H. Egelman* and Jeffrey D. Hartgerink*,
{"title":"A Collagen Triple Helix without the Superhelical Twist","authors":"Mark A. B. Kreutzberger, Le Tracy Yu, Thi H. Bui, Maria C. Hancu, Michael D. Purdy, Tomasz Osinski, Peter M. Kasson, Edward H. Egelman* and Jeffrey D. Hartgerink*, ","doi":"10.1021/acscentsci.5c0001810.1021/acscentsci.5c00018","DOIUrl":"https://doi.org/10.1021/acscentsci.5c00018https://doi.org/10.1021/acscentsci.5c00018","url":null,"abstract":"<p >Collagens are ubiquitous in biology: functioning as the backbone of the extracellular matrix, forming the primary structural components of key immune system complexes, and fulfilling numerous other structural roles in a variety of systems. Despite this, there is limited understanding of how triple helices, the basic collagen structural units, pack into collagenous assemblies. Here we use a peptide self-assembly system to design collagenous assemblies based on the C1q collagen-like region. Using cryo-EM we solved a structure of one assembly to 3.5 Å resolution and built an atomic model. From this, we identify a triple helix conformation with no superhelical twist, starkly in contrast to the canonical right-handed triple helix. This nontwisting region allows for unique hydroxyproline stacking between adjacent triple helices and also results in the formation of an exposed cavity with rings of hydrophobic amino acids packed symmetrically. We find no precedent for such an arrangement of collagen triple helices and designed assemblies with substituted amino acids in various locations to probe key stabilizing amino acid interactions in the complex. The stability of these altered complexes behaves as predicted by our atomic model. Our findings, combined with the extremely limited experimental structural data on triple helix packing in the literature, suggest that collagen and collagen-like assemblies may adopt a far more varied conformational landscape than previously appreciated. We hypothesize that this is particularly likely in packed assemblies of triple helices, adjacent to the termini of these helices and at discontinuities in the required Xaa-Yaa-Gly repeating primary sequence, a discontinuity found in the majority of this class of proteins and in many collagen-associated diseases.</p><p >The atomic structure of the N-terminal domain of C1q was solved using cryo-EM. This revealed collagen triple helices lacking the canonical superhelical twist, a folding motif not previously observed.</p>","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"11 2","pages":"331–345 331–345"},"PeriodicalIF":12.7,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acscentsci.5c00018","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143486921","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ACS Central SciencePub Date : 2025-01-30eCollection Date: 2025-03-26DOI: 10.1021/acscentsci.4c01698
Alexandra D Kent, Jacob G Robins, Isaac J Knudson, Jessica T Vance, Alexander C Solivan, Noah X Hamlish, Katelyn A Fitzgerald, Alanna Schepartz, Scott J Miller, Jamie H D Cate
{"title":"Thioesters Support Efficient Protein Biosynthesis by the Ribosome.","authors":"Alexandra D Kent, Jacob G Robins, Isaac J Knudson, Jessica T Vance, Alexander C Solivan, Noah X Hamlish, Katelyn A Fitzgerald, Alanna Schepartz, Scott J Miller, Jamie H D Cate","doi":"10.1021/acscentsci.4c01698","DOIUrl":"10.1021/acscentsci.4c01698","url":null,"abstract":"<p><p>Thioesters are critical chemical intermediates in numerous extant biochemical reactions and are invoked as key reagents during prebiotic peptide synthesis on an evolving Earth. Here we asked if a thioester could replace the native oxo-ester in acyl-tRNA substrates during protein biosynthesis by the ribosome. We prepared 3'-thio-3'-deoxyadenosine triphosphate in 10 steps from xylose and demonstrated that it is an effective substrate for the <i>Escherichia coli</i> CCA-adding enzyme, which appends 3'-thio-3'-deoxyadenosine to truncated tRNAs ending with 3'-CC. Using a variety of aminoacyl-tRNA synthetases, flexizymes, or a direct thioester exchange reaction, we prepared a suite of 3'-thio-tRNAs acylated with α- and non-α-amino acids. All were recognized and utilized by wild-type <i>E. coli</i> ribosomes during <i>in vitro</i> translation reactions to generate oligopeptides in yields commensurate with native oxo-ester tRNAs. These results indicate that thioester intermediates widely used in Nature can be co-opted to support the incorporation of natural α-amino acids as well as noncanonical monomers by the extant translational machinery for sequence-defined polymer synthesis.</p>","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"11 3","pages":"404-412"},"PeriodicalIF":12.7,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11950863/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750246","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ACS Central SciencePub Date : 2025-01-30DOI: 10.1021/acscentsci.4c0169810.1021/acscentsci.4c01698
Alexandra D. Kent, Jacob G. Robins, Isaac J. Knudson, Jessica T. Vance, Alexander C. Solivan, Noah X. Hamlish, Katelyn A. Fitzgerald, Alanna Schepartz*, Scott J. Miller* and Jamie H. D. Cate*,
{"title":"Thioesters Support Efficient Protein Biosynthesis by the Ribosome","authors":"Alexandra D. Kent, Jacob G. Robins, Isaac J. Knudson, Jessica T. Vance, Alexander C. Solivan, Noah X. Hamlish, Katelyn A. Fitzgerald, Alanna Schepartz*, Scott J. Miller* and Jamie H. D. Cate*, ","doi":"10.1021/acscentsci.4c0169810.1021/acscentsci.4c01698","DOIUrl":"https://doi.org/10.1021/acscentsci.4c01698https://doi.org/10.1021/acscentsci.4c01698","url":null,"abstract":"<p >Thioesters are critical chemical intermediates in numerous extant biochemical reactions and are invoked as key reagents during prebiotic peptide synthesis on an evolving Earth. Here we asked if a thioester could replace the native oxo-ester in acyl-tRNA substrates during protein biosynthesis by the ribosome. We prepared 3′-thio-3′-deoxyadenosine triphosphate in 10 steps from xylose and demonstrated that it is an effective substrate for the <i>Escherichia coli</i> CCA-adding enzyme, which appends 3′-thio-3′-deoxyadenosine to truncated tRNAs ending with 3′-CC. Using a variety of aminoacyl-tRNA synthetases, flexizymes, or a direct thioester exchange reaction, we prepared a suite of 3′-thio-tRNAs acylated with α- and non-α-amino acids. All were recognized and utilized by wild-type <i>E. coli</i> ribosomes during <i>in vitro</i> translation reactions to generate oligopeptides in yields commensurate with native oxo-ester tRNAs. These results indicate that thioester intermediates widely used in Nature can be co-opted to support the incorporation of natural α-amino acids as well as noncanonical monomers by the extant translational machinery for sequence-defined polymer synthesis.</p><p >We show that tRNAs acylated with a thioester rather than an ester linkage to natural and unnatural monomers can be used by the extant translation machinery for sequence-defined polymer synthesis.</p>","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"11 3","pages":"404–412 404–412"},"PeriodicalIF":12.7,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acscentsci.4c01698","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143696464","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ACS Central SciencePub Date : 2025-01-28DOI: 10.1021/acscentsci.5c0004910.1021/acscentsci.5c00049
Diana Kruzman,
{"title":"Metalplant Farms Chemicals for the Clean Energy Transition","authors":"Diana Kruzman, ","doi":"10.1021/acscentsci.5c0004910.1021/acscentsci.5c00049","DOIUrl":"https://doi.org/10.1021/acscentsci.5c00049https://doi.org/10.1021/acscentsci.5c00049","url":null,"abstract":"<p >The phytomining start-up is using plants to extract nickel from Albania’s soil.</p>","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"11 2","pages":"170–172 170–172"},"PeriodicalIF":12.7,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acscentsci.5c00049","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143486805","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ACS Central SciencePub Date : 2025-01-24DOI: 10.1021/acscentsci.4c0194110.1021/acscentsci.4c01941
Suxing Jin, Yafeng He, Chenyao Feng, Jian Yuan, Yan Guo, Zijian Guo and Xiaoyong Wang,
{"title":"Cellular Discrepancy of Platinum Complexes in Interfering with Mitochondrial DNA","authors":"Suxing Jin, Yafeng He, Chenyao Feng, Jian Yuan, Yan Guo, Zijian Guo and Xiaoyong Wang, ","doi":"10.1021/acscentsci.4c0194110.1021/acscentsci.4c01941","DOIUrl":"https://doi.org/10.1021/acscentsci.4c01941https://doi.org/10.1021/acscentsci.4c01941","url":null,"abstract":"<p >Mitochondria are associated with cellular energy metabolism, proliferation, and mode of death. Damage to mitochondrial DNA (mtDNA) greatly affects mitochondrial function by interfering with energy production and the signaling pathway. Monofunctional trinuclear platinum complex MTPC demonstrates different actions on the mtDNA of cancerous and normal cells. It severely impairs the integrity and function of mitochondria in the human lung cancer A549 cells, such as dissipating mitochondrial membrane potential, decreasing the copy number of mtDNA, interfering in nucleoid proteins and polymerase gamma gene, reducing adenosine triphosphate (ATP), and inducing mitophagy, whereas it barely affects the mtDNA of the human kidney 2 (HK-2) cells. Moreover, MTPC promotes the release of mtDNA into the cytosol and stimulates the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, thus showing the potential to trigger antitumor immunity. MTPC displays significant cytotoxicity against A549 cells, while it exhibits weak toxicity toward HK-2 cells, therefore displaying great advantage to overcome the lingering nephrotoxicity of platinum anticancer drugs. Discrepant effects of a metal complex on mitochondria of different cells mean that targeting mitochondria has special significance in cancer therapy.</p><p >Pt complex induces distinct mtDNA damage and death mode in different cell types, causes lesion to mitochondrial integrity and function, activates the cGAS-STING pathway, and reduces nephrotoxicity.</p>","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"11 3","pages":"393–403 393–403"},"PeriodicalIF":12.7,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acscentsci.4c01941","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143696462","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ACS Central SciencePub Date : 2025-01-24eCollection Date: 2025-03-26DOI: 10.1021/acscentsci.4c01941
Suxing Jin, Yafeng He, Chenyao Feng, Jian Yuan, Yan Guo, Zijian Guo, Xiaoyong Wang
{"title":"Cellular Discrepancy of Platinum Complexes in Interfering with Mitochondrial DNA.","authors":"Suxing Jin, Yafeng He, Chenyao Feng, Jian Yuan, Yan Guo, Zijian Guo, Xiaoyong Wang","doi":"10.1021/acscentsci.4c01941","DOIUrl":"10.1021/acscentsci.4c01941","url":null,"abstract":"<p><p>Mitochondria are associated with cellular energy metabolism, proliferation, and mode of death. Damage to mitochondrial DNA (mtDNA) greatly affects mitochondrial function by interfering with energy production and the signaling pathway. Monofunctional trinuclear platinum complex MTPC demonstrates different actions on the mtDNA of cancerous and normal cells. It severely impairs the integrity and function of mitochondria in the human lung cancer A549 cells, such as dissipating mitochondrial membrane potential, decreasing the copy number of mtDNA, interfering in nucleoid proteins and polymerase gamma gene, reducing adenosine triphosphate (ATP), and inducing mitophagy, whereas it barely affects the mtDNA of the human kidney 2 (HK-2) cells. Moreover, MTPC promotes the release of mtDNA into the cytosol and stimulates the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, thus showing the potential to trigger antitumor immunity. MTPC displays significant cytotoxicity against A549 cells, while it exhibits weak toxicity toward HK-2 cells, therefore displaying great advantage to overcome the lingering nephrotoxicity of platinum anticancer drugs. Discrepant effects of a metal complex on mitochondria of different cells mean that targeting mitochondria has special significance in cancer therapy.</p>","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"11 3","pages":"393-403"},"PeriodicalIF":12.7,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11950849/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750215","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ACS Central SciencePub Date : 2025-01-22eCollection Date: 2025-02-26DOI: 10.1021/acscentsci.4c01628
Michael P Mulligan, Matthew W Boudreau, Brooke A Bouwens, Yoongyeong Lee, Hunter W Carrell, Junyao Zhu, Spyro Mousses, David J Shapiro, Erik R Nelson, Timothy M Fan, Paul J Hergenrother
{"title":"Single Dose of a Small Molecule Leads to Complete Regressions of Large Breast Tumors in Mice.","authors":"Michael P Mulligan, Matthew W Boudreau, Brooke A Bouwens, Yoongyeong Lee, Hunter W Carrell, Junyao Zhu, Spyro Mousses, David J Shapiro, Erik R Nelson, Timothy M Fan, Paul J Hergenrother","doi":"10.1021/acscentsci.4c01628","DOIUrl":"10.1021/acscentsci.4c01628","url":null,"abstract":"<p><p>Patients with estrogen receptor α positive (ERα+) breast cancer typically undergo surgical resection, followed by 5-10 years of treatment with adjuvant endocrine therapy. This prolonged intervention is associated with a host of undesired side effects that reduce patient compliance, and ultimately therapeutic resistance and disease relapse/progression are common. An ideal anticancer therapy would be effective against recurrent and refractory disease with minimal dosing; however, there is little precedent for marked tumor regression with a single dose of a small molecule therapeutic. Herein we report <b>ErSO-TFPy</b> as a small molecule that induces quantitative or near-quantitative regression of tumors in multiple mouse models of breast cancer with a single dose. Importantly, this effect is robust and independent of tumor size with eradication of even very large tumors (500-1500 mm<sup>3</sup>) observed. Mechanistically, these tumor regressions are a consequence of rapid induction of necrotic cell death in the tumor and are immune cell independent. If successfully translated to human cancer patients, the benefits of such an anticancer drug that is effective with a single dose would be significant.</p>","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"11 2","pages":"228-238"},"PeriodicalIF":12.7,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11869136/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143539348","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ACS Central SciencePub Date : 2025-01-22DOI: 10.1021/acscentsci.4c0162810.1021/acscentsci.4c01628
Michael P. Mulligan, Matthew W. Boudreau, Brooke A. Bouwens, Yoongyeong Lee, Hunter W. Carrell, Junyao Zhu, Spyro Mousses, David J. Shapiro, Erik R. Nelson, Timothy M. Fan and Paul J. Hergenrother*,
{"title":"Single Dose of a Small Molecule Leads to Complete Regressions of Large Breast Tumors in Mice","authors":"Michael P. Mulligan, Matthew W. Boudreau, Brooke A. Bouwens, Yoongyeong Lee, Hunter W. Carrell, Junyao Zhu, Spyro Mousses, David J. Shapiro, Erik R. Nelson, Timothy M. Fan and Paul J. Hergenrother*, ","doi":"10.1021/acscentsci.4c0162810.1021/acscentsci.4c01628","DOIUrl":"https://doi.org/10.1021/acscentsci.4c01628https://doi.org/10.1021/acscentsci.4c01628","url":null,"abstract":"<p >Patients with estrogen receptor α positive (ERα+) breast cancer typically undergo surgical resection, followed by 5–10 years of treatment with adjuvant endocrine therapy. This prolonged intervention is associated with a host of undesired side effects that reduce patient compliance, and ultimately therapeutic resistance and disease relapse/progression are common. An ideal anticancer therapy would be effective against recurrent and refractory disease with minimal dosing; however, there is little precedent for marked tumor regression with a single dose of a small molecule therapeutic. Herein we report <b>ErSO-TFPy</b> as a small molecule that induces quantitative or near-quantitative regression of tumors in multiple mouse models of breast cancer with a single dose. Importantly, this effect is robust and independent of tumor size with eradication of even very large tumors (500−1500 mm<sup>3</sup>) observed. Mechanistically, these tumor regressions are a consequence of rapid induction of necrotic cell death in the tumor and are immune cell independent. If successfully translated to human cancer patients, the benefits of such an anticancer drug that is effective with a single dose would be significant.</p><p >A single dose of <b>ErSO-TFPy</b> leads to complete tumor regressions in multiple mouse xenograft models of breast cancer.</p>","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"11 2","pages":"228–238 228–238"},"PeriodicalIF":12.7,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acscentsci.4c01628","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143486800","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ACS Central SciencePub Date : 2025-01-17eCollection Date: 2025-02-26DOI: 10.1021/acscentsci.4c02060
Geetika Dhanda, Himani Singh, Abhinav Gupta, Sk Abdul Mohid, Karishma Biswas, Riya Mukherjee, Smriti Mukherjee, Anirban Bhunia, Nisanth N Nair, Jayanta Haldar
{"title":"Dual-Functional Antibiotic Adjuvant Displays Potency against Complicated Gram-Negative Bacterial Infections and Exhibits Immunomodulatory Properties.","authors":"Geetika Dhanda, Himani Singh, Abhinav Gupta, Sk Abdul Mohid, Karishma Biswas, Riya Mukherjee, Smriti Mukherjee, Anirban Bhunia, Nisanth N Nair, Jayanta Haldar","doi":"10.1021/acscentsci.4c02060","DOIUrl":"https://doi.org/10.1021/acscentsci.4c02060","url":null,"abstract":"<p><p>The treatment of Gram-negative bacterial infections is challenged by antibiotic resistance and complicated forms of infection like persistence, multispecies biofilms, intracellular infection, as well as infection-associated hyperinflammation and sepsis. To overcome these challenges, a dual-functional antibiotic adjuvant has been developed as a novel strategy to target complicated forms of bacterial infection and exhibit immunomodulatory properties. The lead adjuvant, D-LBDiphe showed multimodal mechanisms of action like weak outer membrane permeabilization, weak membrane depolarization, and inhibition of efflux machinery, guided primarily by hydrogen bonding and electrostatic interactions, along with weak van der Waals forces. D-LBDiphe potentiated antibiotics up to ∼4100-fold, targeted phenotypic forms of antibiotic tolerance, and revitalized antibiotics against topical and systemic infections of <i>P. aeruginosa</i> in mice. The aromatic moiety in D-LBDiphe was instrumental for interaction with lipopolysaccharide (LPS) micelles, and this interaction was the driving factor in reducing pro-inflammatory cytokines by 61.8-79% in mice challenged with LPS. Such multifarious properties of a weak-membrane perturbing, nonactive and nontoxic adjuvant have been discussed for the first time, supported by detailed mechanistic understanding and elucidation of structure-guided properties. This work expands the scope of antibiotic adjuvants and validates them as a promising approach for treatment of complicated bacterial infections and inflammation.</p>","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"11 2","pages":"279-293"},"PeriodicalIF":12.7,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11868958/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143539388","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ACS Central SciencePub Date : 2025-01-17DOI: 10.1021/acscentsci.4c0206010.1021/acscentsci.4c02060
Geetika Dhanda, Himani Singh, Abhinav Gupta, Sk Abdul Mohid, Karishma Biswas, Riya Mukherjee, Smriti Mukherjee, Anirban Bhunia, Nisanth N. Nair and Jayanta Haldar*,
{"title":"Dual-Functional Antibiotic Adjuvant Displays Potency against Complicated Gram-Negative Bacterial Infections and Exhibits Immunomodulatory Properties","authors":"Geetika Dhanda, Himani Singh, Abhinav Gupta, Sk Abdul Mohid, Karishma Biswas, Riya Mukherjee, Smriti Mukherjee, Anirban Bhunia, Nisanth N. Nair and Jayanta Haldar*, ","doi":"10.1021/acscentsci.4c0206010.1021/acscentsci.4c02060","DOIUrl":"https://doi.org/10.1021/acscentsci.4c02060https://doi.org/10.1021/acscentsci.4c02060","url":null,"abstract":"<p >The treatment of Gram-negative bacterial infections is challenged by antibiotic resistance and complicated forms of infection like persistence, multispecies biofilms, intracellular infection, as well as infection-associated hyperinflammation and sepsis. To overcome these challenges, a dual-functional antibiotic adjuvant has been developed as a novel strategy to target complicated forms of bacterial infection and exhibit immunomodulatory properties. The lead adjuvant, D-LBDiphe showed multimodal mechanisms of action like weak outer membrane permeabilization, weak membrane depolarization, and inhibition of efflux machinery, guided primarily by hydrogen bonding and electrostatic interactions, along with weak van der Waals forces. D-LBDiphe potentiated antibiotics up to ∼4100-fold, targeted phenotypic forms of antibiotic tolerance, and revitalized antibiotics against topical and systemic infections of <i>P. aeruginosa</i> in mice. The aromatic moiety in D-LBDiphe was instrumental for interaction with lipopolysaccharide (LPS) micelles, and this interaction was the driving factor in reducing pro-inflammatory cytokines by 61.8–79% in mice challenged with LPS. Such multifarious properties of a weak-membrane perturbing, nonactive and nontoxic adjuvant have been discussed for the first time, supported by detailed mechanistic understanding and elucidation of structure-guided properties. This work expands the scope of antibiotic adjuvants and validates them as a promising approach for treatment of complicated bacterial infections and inflammation.</p><p >D-LBDiphe is a dual-functional antibiotic adjuvant which potentiates antibiotics against complicated Gram-negative bacterial infections and reduces bacterial lipopolysaccharide induced inflammation.</p>","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"11 2","pages":"279–293 279–293"},"PeriodicalIF":12.7,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acscentsci.4c02060","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143486760","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}