ACS Infectious Diseases最新文献

{"title":"Antimicrobial Peptides Can Facilitate Whole Blood Safety from Bacteria: A Proof of Concept","authors":"Supaksorn Chattagul,&nbsp;Joseph Jackson,&nbsp;William C. Wimley and Chintamani Atreya*,&nbsp;","doi":"10.1021/acsinfecdis.5c00363","DOIUrl":"10.1021/acsinfecdis.5c00363","url":null,"abstract":"<p >With continuous improvements to blood donor deferrals and the availability of sensitive tests for donation screening for infectious agents, bacterial contamination of whole blood (WB) and blood components stored for transfusion is a rare event. Nonetheless, it still occurs and remains a transfusion-associated risk in terms of septic transfusion reactions (STRs) and transfusion-transmitted bacterial infections with morbidity and mortality outcomes. One of the risk mitigation strategies for bacterial contamination is to implement treatment with currently available proactive pathogen reduction technologies (PRTs) for these transfusion products. Here, as a proof of concept, we tested two recently developed unique cationic antimicrobial peptides (AMPs; D-CONGA and D-CONGA-Q7) for WB safety from bacterial contamination. In this study, WB was inoculated with <i>Escherichia coli</i> and <i>Staphylococcus epidermidis</i> and treated with the two peptides to evaluate their bactericidal efficacy. The results demonstrated that D-CONGA and D-CONGA-Q7 exhibit potent inhibitory activity against the bacteria with a minimal inhibitory concentration (MIC) range of 4–8 and 1–8 μM, respectively, depending on the bacterial species tested. Time-kill kinetics further confirmed that the peptides exhibit bactericidal efficacy at 8 μM by achieving a 5-log₁₀ reduction (99.999%) of the bacterial load in WB with a time-dependent killing profile. Furthermore, even at 20 μM, the AMPs did not negatively impact hemolysis or hemostatic properties. We have further demonstrated using a cationic exchange resin that the cationic AMPs can be separated and removed from WB after the peptide treatments. During 35-day WB storage at 2–8 °C, 4 μM D-CONGA-Q7 one-time treatment prevented <i>S. epidermidis</i> growth and preserved WB quality and integrity. Overall, the results described here provide the first proof of concept that certain AMPs, such as D-CONGA and D-CONGA-Q7, can facilitate WB safety from bacteria during storage.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"11 8","pages":"2323–2330"},"PeriodicalIF":3.8,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsinfecdis.5c00363","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144740615","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GaSal-2: A Water-Soluble Antipseudomonal Agent Targeting the Extracellular Hemophore HasAp","authors":"Aziza Frank,&nbsp;Lucia Hwang,&nbsp;William T. Witt,&nbsp;Garrick Centola,&nbsp;Kieran Johnson,&nbsp;Yong Ai,&nbsp;Emel Sen-Kilic,&nbsp;Gage M. Pyles,&nbsp;Annalisa B. Huckaby,&nbsp;Catherine B. Blackwood,&nbsp;Sarah Jo Miller,&nbsp;S. Matthew Hudson,&nbsp;Kellie Hom,&nbsp;Wenbo Yu,&nbsp;Alexander D. MacKerell Jr.,&nbsp;Mariette Barbier,&nbsp;Angela Wilks* and Fengtian Xue*,&nbsp;","doi":"10.1021/acsinfecdis.5c00296","DOIUrl":"10.1021/acsinfecdis.5c00296","url":null,"abstract":"<p >Multidrug-resistant <i>Pseudomonas aeruginosa</i> is a critical pathogen that demands new antibiotics. During <i>P. aeruginosa</i> infection, the extracellular hemophore <i>hasAp</i> and its outer membrane receptor <i>hasR</i> are the most dramatically upregulated genes. The <i>P. aeruginosa</i> Δ<i>hasR</i> strain exhibits significantly reduced growth and virulence. We previously described a gallium salophen complex GaSal that demonstrated antipseudomonal potential by targeting HasAp. Here, we report the development of a water-soluble derivative, GaSal-2, which tightly binds to HasAp, blocks transcriptional activation of the bacterial cell surface signaling cascade, inhibits <i>P. aeruginosa</i> growth, and effectively disrupts <i>P. aeruginosa</i> established biofilms. Moreover, GaSal-2 is not toxic to human lung fibroblasts and hepatocytes. It has shown promising antipseudomonal effects in a murine lung infection model.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"11 8","pages":"2287–2300"},"PeriodicalIF":3.8,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144740616","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibitor Affinity Differs among Clinical Variants of IMP Metallo-β-Lactamases: Analysis and Implications for Inhibitor Design","authors":"Caitlyn A. Thomas*,&nbsp;John Paul Alao,&nbsp;Thomas Smisek,&nbsp;Zishuo Cheng,&nbsp;Christopher R. Bethel,&nbsp;Kundi Yang,&nbsp;Ikponwmosa Obaseki,&nbsp;Richard C. Page,&nbsp;Robert A. Bonomo,&nbsp;Peter Oelschlaeger,&nbsp;Walter Fast,&nbsp;Andrea N. Kravats and Michael W. Crowder,&nbsp;","doi":"10.1021/acsinfecdis.5c00138","DOIUrl":"10.1021/acsinfecdis.5c00138","url":null,"abstract":"<p >β-Lactam-resistant bacterial infections are a serious concern worldwide. A common mechanism of β-lactam resistance is the expression of β-lactamases, which are capable of hydrolyzing the β-lactam bond in the most commonly used β-lactam antibiotics. Metallo-β-lactamases (MBLs) utilize 1 or 2 zinc ions for catalysis. One of the three most clinically relevant MBLs is Imipenemase (IMP). An important potential way to combat MBLs is to use an inhibitor in combination with an existing β-lactam drug. The current study investigates the mechanism of inhibition of preclinical boronic acid β-lactamase inhibitor RPX 7546 and mercaptomethyl bisthiazolidine D-CS319, which are two previously reported MBL inhibitors, with IMP-1 and its variant IMP-78 (V67F/S262G), chosen due to its improved efficiency hydrolyzing carbapenem β-lactams. A combination of analytical and biochemical experiments and <i>in silico</i> modeling collectively offer a comprehensive understanding of the mechanism of inhibition by these two inhibitors. Our studies show that RPX 7546 is a less effective inhibitor of IMP-78, compared to IMP-1, while D-CS319 shows equally effective inhibition of both enzymes. The findings can be explained in light of the evolution of IMP-78 to overcome structural differences of substrates. Studying inhibitors with variants of clinically relevant MBLs is an area that is growing in importance in the literature. The findings of the current study highlight its significance and the urgent need for the discovery of an MBL inhibitor for clinical use.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"11 8","pages":"2157–2168"},"PeriodicalIF":3.8,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144697083","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of Broad-Spectrum Antimicrobial Peptides through the Conjugation of FtsZ-Binding and Cell-Penetrating Peptides","authors":"Ruo-Lan Du,&nbsp;Cheung-Hin Hung,&nbsp;Alan Siu-Lun Leung,&nbsp;Kang Ding,&nbsp;Wai-Po Kong,&nbsp;Yong Wang,&nbsp;Zhi-Guang Liang,&nbsp;Pak-Ho Chan and Kwok-Yin Wong*,&nbsp;","doi":"10.1021/acsinfecdis.5c00220","DOIUrl":"10.1021/acsinfecdis.5c00220","url":null,"abstract":"<p >The rapid increase in bacterial resistance to conventional antibiotics has led to a great demand for novel antibacterial agents. Antimicrobial peptides (AMPs) are emerging as next-generation antimicrobial alternative drugs to conventional antibiotics because of their broad-spectrum antimicrobial activities and minimal potential for drug resistance induction. This work describes novel antimicrobial peptides (FtsZpcpp) synthesized through the conjugation of a cell penetration peptide ((RXR)₄XB) to nonantimicrobial peptides (FtsZp). The FtsZp peptides were previously identified to bind FtsZ (flaming-temperature-sensitive protein Z), a crucial protein in regulating bacterial cell divisions. Newly designed FtsZpcpp peptides have broad antimicrobial activities against both Gram-positive and Gram-negative bacteria, including multidrug-resistant strains. Besides, these new peptides exert minimal hemolytic activity toward human red blood cells and low cytotoxicity toward human skin cells. Comprehensive studies on the antimicrobial mechanism of FtsZpcpp peptides revealed that they exert antimicrobial activities through multiple mechanisms, including membrane disruption and intracellular actions (e.g., interference with cell divisions, DNA binding, and reactive oxygen species (ROS) generation). Our results have shown that FtsZpcpp peptides have the potential to serve as future antimicrobial drugs in combating the increasing global problem of antibiotic resistance.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"11 8","pages":"2190–2204"},"PeriodicalIF":3.8,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsinfecdis.5c00220","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144705745","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural Basis for Postfusion-Specific Binding to the Respiratory Syncytial Virus F Protein by the Canonical Antigenic Site I Antibody 131–2a","authors":"Weiwei Peng,&nbsp;Marta Šiborová,&nbsp;Xuesheng Wu,&nbsp;Wenjuan Du,&nbsp;Douwe Schulte,&nbsp;Matti F. Pronker,&nbsp;Cornelis A. M. de Haan and Joost Snijder*,&nbsp;","doi":"10.1021/acsinfecdis.5c00368","DOIUrl":"10.1021/acsinfecdis.5c00368","url":null,"abstract":"<p >The respiratory syncytial virus (RSV) fusion (F) protein is a major target of antiviral antibodies following natural infection or vaccination and is responsible for mediating fusion between the viral envelope and the host membrane. The fusion process is driven by a large-scale conformational change in F, switching irreversibly from the metastable prefusion state to the stable postfusion conformation. Previous research has identified six distinct antigenic sites in RSV-F, termed sites Ø, I, II, III, IV, and V. Of these, only antigenic site I is fully specific to the postfusion conformation of F. A monoclonal antibody 131–2a that specifically targets postfusion F has been widely used as a research tool to probe for postfusion F and to define antigenic site I in serological studies, yet its sequence and precise epitope have remained unknown. Here, we use mass spectrometry-based <i>de novo</i> sequencing of 131–2a to reverse engineer a recombinant product and study the epitope to define antigenic site I with molecular detail, revealing the structural basis for the antibody’s specificity toward postfusion RSV-F.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"11 8","pages":"2357–2366"},"PeriodicalIF":3.8,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsinfecdis.5c00368","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144688318","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Studies on Developing a Preclinical Candidate to Fight Helicobacter Pylori Infection","authors":"Haritha Dilip,&nbsp;Deepika Khasa,&nbsp;Ramya V K,&nbsp;Parvinder Kaur,&nbsp;Siva Shanmugam,&nbsp;Naveenkumar Chakenalli,&nbsp;Radhakrishanan Shandil,&nbsp;Shridhar Narayanan,&nbsp;Vijay Thiruvenkatam and Sivapriya Kirubakaran*,&nbsp;","doi":"10.1021/acsinfecdis.5c00383","DOIUrl":"10.1021/acsinfecdis.5c00383","url":null,"abstract":"<p ><i>Helicobacter pylori</i> (<i>H. pylori</i>) infection, a precursor to gastritis and gastric cancer, is one of the many infectious diseases that pose a challenge to the progress of developing nations. The present study is the first report on the development of a set of benzopyridine-fused benzimidazoles, leading to the identification of a lead and its further optimization as a potential preclinical candidate for treating <i>H. pylori</i> infection. The designed synthetic method for these derivatives is devoid of toxic chemicals and sophisticated reaction setups, using economical and readily available chemicals to produce benzopyridine-fused (namely, quinoline/isoquinoline-fused) benzimidazole derivatives in moderate-to-good yields. These small molecules showed promising <i>H. pylori</i> growth inhibition, and a lead molecule was identified and evaluated for its antibacterial potential. Following the promising results of the growth inhibition displayed by this series of inhibitors, lead optimization studies were carried out on the best inhibitor of <i>H. pylori</i> growth, highlighting the possibility of developing this core molecule for preclinical trials.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"11 8","pages":"2367–2371"},"PeriodicalIF":3.8,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144666639","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Netupitant Exhibits Potent Activity on Mycobacterium tuberculosis Persisters","authors":"Hassan E. Eldesouky,&nbsp;Richard M. Jones,&nbsp;Shabber Mohammed,&nbsp;Enming Xing,&nbsp;Pui-Kai Li and David R. Sherman*,&nbsp;","doi":"10.1021/acsinfecdis.5c00298","DOIUrl":"10.1021/acsinfecdis.5c00298","url":null,"abstract":"<p >In <i>Mycobacterium tuberculosis</i> (Mtb), persisters are genotypically drug-sensitive bacteria that nonetheless survive antibiotic treatment. Persisters contribute to prolonged TB treatment duration and relapse risk, highlighting the need for new therapeutic strategies to effectively eliminate these tolerant subpopulations. In this study, we screened 2,336 FDA-approved compounds to identify agents that enhance the sterilizing activity of standard anti-TB drugs and prevent the regrowth of persisters. Netupitant (NTP), an FDA-approved antiemetic, emerged as a promising candidate. In combination with isoniazid (INH) and rifampicin (RIF), NTP eliminated viable Mtb cells, achieving a &gt;6-log reduction in colony-forming units (CFUs), compared to the 2.5-log reduction observed with INH-RIF alone. NTP also demonstrated broad-spectrum efficacy, enhancing the activity of multiple TB drugs, including ethambutol, moxifloxacin, amikacin, and bedaquiline. Notably, NTP retained its potency under hypoxic and caseum-mimicking conditions, both of which are known to enrich for non-replicating, drug-tolerant cells. The mammalian target of NTP, the G protein-coupled receptor NK-1, is absent in bacteria, raising the possibility that the NTP target in bacteria is novel. To begin assessing this possibility, we performed transcriptomics and found that NTP significantly upregulates multiple oxidative stress response-associated genes, while downregulating pathways linked to protein synthesis, electron transport chain activities, and ATP synthesis. While further studies are required to decipher mechanisms of action and the resistance profile of NTP, and to assess its in vivo efficacy, these findings underscore its potential as a promising adjunct to existing TB therapies.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"11 8","pages":"2265–2275"},"PeriodicalIF":3.8,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144657835","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enantioselective Chemical Probe for Chikungunya nsP2 Helicase with Antialphaviral Activity","authors":"Bose Muthu Ramalingam,&nbsp;Hans J. Oh,&nbsp;John D. Sears,&nbsp;Chun-Hsing Chen,&nbsp;Anand Vala,&nbsp;Shubin Liu,&nbsp;Kacey M. Talbot,&nbsp;Mohammed Anwar Hossain,&nbsp;Peter J. Brown,&nbsp;Scott Houliston,&nbsp;Julia Garcia Perez,&nbsp;Fengling Li,&nbsp;Meareg G. Amare,&nbsp;Peter Halfmann,&nbsp;Jessica L. Smith,&nbsp;Alec J. Hirsch,&nbsp;Cheryl H. Arrowsmith,&nbsp;Levon Halabelian,&nbsp;Ava Vargason,&nbsp;Rafael M. Couñago,&nbsp;Jamie J. Arnold,&nbsp;Craig E. Cameron,&nbsp;Nathaniel J. Moorman,&nbsp;Mark T. Heise and Timothy M. Willson*,&nbsp;","doi":"10.1021/acsinfecdis.5c00351","DOIUrl":"10.1021/acsinfecdis.5c00351","url":null,"abstract":"<p >Chikungunya virus (CHIKV) replication relies on the multifunctional nsP2 protein, making it an attractive target for antiviral drug discovery. Here, we report the resolution of oxaspiropiperidine <b>1</b>, a first-in-class inhibitor of the CHIKV nsP2 RNA helicase (nsP2hel), into its constitutive enantiomers and characterization of their antiviral activity. The enantiomer (<i>R</i>)-<b>1</b> exhibited potent inhibition of viral replication, nsP2hel ATPase activity, and dsRNA unwinding, while the (<i>S</i>)-<b>1</b> enantiomer was &gt;100-fold less active. The (<i>R</i>)-<b>1</b> enantiomer also demonstrated a high selectivity for CHIKV over other RNA viruses and for nsP2hel over other RNA helicases. Direct binding of (<i>R</i>)-<b>1</b> to the nsP2hel protein was confirmed by ¹⁹F NMR. Biophysical and structural studies revealed conformational polymorphism in the spirocyclic scaffold of (<i>R</i>)-<b>1</b>, suggesting a potential role of thermal mobility of the ligand in allosteric inhibition of nsP2hel. Collectively, these findings designate (<i>R</i>)-<b>1</b> (RA-NSP2-<b>1</b>) as a high-quality chemical probe and (<i>S</i>)-<b>1</b> (RA-NSP2-<b>1</b>N) as a negative control for probing the biology of alphavirus RNA helicases.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"11 8","pages":"2331–2341"},"PeriodicalIF":3.8,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsinfecdis.5c00351","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144663837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification and Evaluation of Non-Nucleosidic MTase Inhibitors against SARS-CoV-2 nsp14 with Lower-Micromolar Anti-Coronavirus Activity","authors":"Yuanmei Wen,&nbsp;Jun Zhou,&nbsp;Fan Pan,&nbsp;Peisen Zheng,&nbsp;Fengxia Zhong,&nbsp;Sidi Yang,&nbsp;Qianhan Ma,&nbsp;Deyin Guo,&nbsp;Xumu Zhang,&nbsp;Qifan Zhou* and Yingjun Li*,&nbsp;","doi":"10.1021/acsinfecdis.4c01044","DOIUrl":"10.1021/acsinfecdis.4c01044","url":null,"abstract":"<p >Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes respiratory infections ranging from mild to severe, posing significant public health risks. The emergence of new variants highlights the need for inhibitors targeting conserved nonstructural proteins like nsp14, a key <i>N</i>7-methyltransferase (MTase) critical for viral RNA capping, immune evasion, and replication. Here, we screened 131 compounds using a drug repurposing approach and identified five candidates that inhibit MTase activity. Bobcat339 showed significant inhibition (IC₅₀ = 21.6 μM) and binding affinity (Δ<i>T</i>_m = +3.9 °C). It also reduced the replication of HCoV-229E and SARS-CoV-2 in infected Huh7 cells (EC₅₀ = 29.8 and 28.4 μM, respectively). Molecular docking suggested Bobcat339 binds the SAM-binding pocket of nsp14 MTase. These results identify Bobcat339 as a promising lead for developing selective, non-nucleoside nsp14 inhibitors, supporting further structural optimization and preclinical evaluation.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"11 8","pages":"2145–2156"},"PeriodicalIF":3.8,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144657834","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of a Widespread Polyamine–Low-Molecular-Weight Thiol Hybrid Pathway in Clostridioides difficile","authors":"Rachelle L. Hunt,&nbsp;Joonseok Oh,&nbsp;Abhishek Jain,&nbsp;Ting-Hao Kuo,&nbsp;Domenica Berardi,&nbsp;Wenya Jian,&nbsp;Deguang Song,&nbsp;Qihao Wu,&nbsp;Andrew L. Goodman,&nbsp;Noah W. Palm,&nbsp;Michael Zimmermann,&nbsp;Caroline H. Johnson and Jason M. Crawford*,&nbsp;","doi":"10.1021/acsinfecdis.5c00286","DOIUrl":"10.1021/acsinfecdis.5c00286","url":null,"abstract":"<p ><i>Clostridioides difficile</i> infection can cause severe inflammation in the gastrointestinal (GI) tract, leading to diarrhea, colitis, and an increased risk of colorectal cancer. Colonization of <i>C. difficile</i> is associated with microbial community-level changes in the expression of polyamine and polyamine precursor biosynthesis genes. Polyamines are abundant cationic metabolites that serve indispensable functions for all kingdoms, particularly in gut homeostasis. Catabolism of the polyamine precursors arginine and ornithine offers <i>C. difficile</i> supplemental nutrition while subverting host immunity, yet existing models of <i>C. difficile</i> metabolism are incomplete regarding polyamines with comparable importance in the gut (e.g., spermidine). In this study, we conducted feeding studies with isotope-labeled polyamines and discovered a network of low-molecular-weight thiol (LMWT) molecules termed clostridithiols (CSHs) constructed from polyamines conjugated with <i>N</i>-acetylcysteine (NAC) moieties. NAC is clinically used as a mucolytic agent and is a well-established redox molecule. Through the analysis of a human microbiota diversity collection, we established that these previously uncharacterized hybrid metabolites are widely detected in Firmicutes and Bacteroidetes. A genetic screen using DNA from an alternative CSH producer<i>Bacteroides uniformis</i> enabled the identification and validation of a two-gene operon, including a gene encoding a domain of unknown function, that was conserved in both producing organisms and other members of the microbiome. CSH abundance in GI mucosal biopsies positively correlated with colorectal cancer compared with matched healthy control samples. These studies indicate that human microbial metabolism broadly unites polyamine and LMWT functionalities to generate metabolites that may be associated with disease.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"11 8","pages":"2246–2264"},"PeriodicalIF":3.8,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144647953","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}