ACS Infectious DiseasesPub Date : 2025-03-18DOI: 10.1021/acsinfecdis.4c0085610.1021/acsinfecdis.4c00856
Sijia Gao, Yonglin He, Xichuan Deng, Nan Lu, Jiajia Bao, Anlong Li, Xintong He, Shiyan He, Nanzhe Fu, Felycia Fernanda Hosyanto and Lei Xu*,
{"title":"Chemokine CXCL14 Inhibits the Survival of Mycobacterium smegmatis inside Macrophages by Upregulating A20 to Promote ROS Production","authors":"Sijia Gao, Yonglin He, Xichuan Deng, Nan Lu, Jiajia Bao, Anlong Li, Xintong He, Shiyan He, Nanzhe Fu, Felycia Fernanda Hosyanto and Lei Xu*, ","doi":"10.1021/acsinfecdis.4c0085610.1021/acsinfecdis.4c00856","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c00856https://doi.org/10.1021/acsinfecdis.4c00856","url":null,"abstract":"<p >Tuberculosis remains a major global health threat, with traditional antibiotic treatments facing challenges such as drug resistance. Host-directed therapy (HDT) has emerged as a promising approach to combat tuberculosis by enhancing the host immune response. CXCL14, a chemokine family member, plays a crucial role in regulating host antipathogenic immune responses. To elucidate the role of CXCL14 and its key regulatory molecules in mycobacterial infections, we identified new targets for host-directed therapy. RAW264.7 macrophages were pretreated with CXCL14 and infected with <i>Mycobacterium smegmatis</i>. CFU, ROS levels, and apoptosis were assessed. Cell RNA was extracted for high-throughput sequencing, and significantly differentially expressed genes were screened and identified. The effects of candidate genes were verified using knockdown and overexpression techniques. A mouse model of mycobacterial infection was established to validate the role of CXCL14 in vivo. CXCL14 pretreatment significantly reduced intracellular mycobacteria and increased ROS levels in macrophages without affecting apoptosis. Transcriptome analysis identified A20 as a key differentially expressed gene. A20 overexpression promoted ROS production and decreased intracellular mycobacteria, while A20 knockdown reversed these effects. The combination of CXCL14 and A20 overexpression effectively inhibited mycobacterial survival in macrophages. CXCL14 significantly inhibited mycobacterial survival in mice and reduced organ damage in vivo. CXCL14 promoted ROS production in macrophages by upregulating A20 expression, thereby inhibiting mycobacterial survival. In the mouse model, CXCL14 alleviated inflammatory responses and histopathological damage caused by mycobacterial infection. These findings suggest that CXCL14 is a promising new HDT molecule for the treatment of mycobacterial infections.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"11 4","pages":"844–858 844–858"},"PeriodicalIF":4.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143814432","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}
ACS Infectious DiseasesPub Date : 2025-03-18DOI: 10.1021/acsinfecdis.4c0094610.1021/acsinfecdis.4c00946
Katerina Dvorakova Bendova, Kristyna Krasulova, Barbora Neuzilova, Miroslav Popper, Patrik Mlynarcik, Katarina Hajduova, Zbynek Novy, Marian Hajduch and Milos Petrik*,
{"title":"Positron Emission Tomography Imaging of Acinetobacter baumannii Infection: Comparison of Gallium-68 Labeled Siderophores","authors":"Katerina Dvorakova Bendova, Kristyna Krasulova, Barbora Neuzilova, Miroslav Popper, Patrik Mlynarcik, Katarina Hajduova, Zbynek Novy, Marian Hajduch and Milos Petrik*, ","doi":"10.1021/acsinfecdis.4c0094610.1021/acsinfecdis.4c00946","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c00946https://doi.org/10.1021/acsinfecdis.4c00946","url":null,"abstract":"<p ><i>Acinetobacter baumannii</i> (AB) is an opportunistic pathogen with growing clinical relevance due to its increasing level of antimicrobial resistance in the last few decades. In the event of an AB hospital outbreak, fast detection and localization of the pathogen is crucial, to prevent its further spread. However, contemporary diagnostic tools do not always meet the requirements for rapid and accurate diagnosis. For this reason, we report here the possibility of using gallium-68 labeled siderophores, bacterial iron chelators, for positron emission tomography imaging of AB infections. In our study, we radiolabeled several siderophores and tested their in vitro uptake in AB cultures. Based on the results and the in vitro properties of studied siderophores, we selected two of them for further in vivo testing in infectious models. Both selected siderophores, ferrioxamine E and ferrirubin, showed promising in vitro characteristics. In vivo, we observed rapid pharmacokinetics and no excessive accumulation in organs other than the excretory organs in normal mice. We demonstrated that the radiolabeled siderophores accumulate in AB-infected tissue in three animal models: a murine model of myositis, a murine model of dorsal wound infection and a rat model of pneumonia. These results suggest that both siderophores radiolabeled with Ga-68 could be used for PET imaging of AB infection.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"11 4","pages":"917–928 917–928"},"PeriodicalIF":4.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsinfecdis.4c00946","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143814468","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}
Katerina Dvorakova Bendova, Kristyna Krasulova, Barbora Neuzilova, Miroslav Popper, Patrik Mlynarcik, Katarina Hajduova, Zbynek Novy, Marian Hajduch, Milos Petrik
{"title":"Positron Emission Tomography Imaging of <i>Acinetobacter baumannii</i> Infection: Comparison of Gallium-68 Labeled Siderophores.","authors":"Katerina Dvorakova Bendova, Kristyna Krasulova, Barbora Neuzilova, Miroslav Popper, Patrik Mlynarcik, Katarina Hajduova, Zbynek Novy, Marian Hajduch, Milos Petrik","doi":"10.1021/acsinfecdis.4c00946","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c00946","url":null,"abstract":"<p><p><i>Acinetobacter baumannii</i> (AB) is an opportunistic pathogen with growing clinical relevance due to its increasing level of antimicrobial resistance in the last few decades. In the event of an AB hospital outbreak, fast detection and localization of the pathogen is crucial, to prevent its further spread. However, contemporary diagnostic tools do not always meet the requirements for rapid and accurate diagnosis. For this reason, we report here the possibility of using gallium-68 labeled siderophores, bacterial iron chelators, for positron emission tomography imaging of AB infections. In our study, we radiolabeled several siderophores and tested their in vitro uptake in AB cultures. Based on the results and the in vitro properties of studied siderophores, we selected two of them for further in vivo testing in infectious models. Both selected siderophores, ferrioxamine E and ferrirubin, showed promising in vitro characteristics. In vivo, we observed rapid pharmacokinetics and no excessive accumulation in organs other than the excretory organs in normal mice. We demonstrated that the radiolabeled siderophores accumulate in AB-infected tissue in three animal models: a murine model of myositis, a murine model of dorsal wound infection and a rat model of pneumonia. These results suggest that both siderophores radiolabeled with Ga-68 could be used for PET imaging of AB infection.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143646467","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":"Standardized Residue Numbering and Secondary Structure Nomenclature in the Class D β-Lactamases.","authors":"Anastasiya Stasyuk, Clyde A Smith","doi":"10.1021/acsinfecdis.5c00060","DOIUrl":"10.1021/acsinfecdis.5c00060","url":null,"abstract":"<p><p>Over 1370 class D β-lactamases are currently known, and they pose a serious threat to the effective treatment of many infectious diseases, particularly in some pathogenic bacteria where evolving carbapenemase activity has been reported. Detailed understanding of their molecular biology, enzymology, and structural biology are critically important, but the lack of a standardized residue numbering scheme and inconsistent secondary structure annotation has made comparative analyses sometimes difficult and cumbersome. Compounding this, in the post-AlphaFold world where we currently find ourselves, an extraordinary wealth of detailed structural information on these enzymes is literally at our fingertips; therefore it is vitally important that a standard numbering system is in place to facilitate the accurate and straightforward analysis of their structures. Here we present a residue numbering and secondary structure scheme for the class D enzymes based on the sequence and structure of OXA-48 and apply it to test targets to demonstrate the ease with which it can be used.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143646468","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}
ACS Infectious DiseasesPub Date : 2025-03-17DOI: 10.1021/acsinfecdis.5c0006010.1021/acsinfecdis.5c00060
Anastasiya Stasyuk, and , Clyde A. Smith*,
{"title":"Standardized Residue Numbering and Secondary Structure Nomenclature in the Class D β-Lactamases","authors":"Anastasiya Stasyuk, and , Clyde A. Smith*, ","doi":"10.1021/acsinfecdis.5c0006010.1021/acsinfecdis.5c00060","DOIUrl":"https://doi.org/10.1021/acsinfecdis.5c00060https://doi.org/10.1021/acsinfecdis.5c00060","url":null,"abstract":"<p >Over 1370 class D β-lactamases are currently known, and they pose a serious threat to the effective treatment of many infectious diseases, particularly in some pathogenic bacteria where evolving carbapenemase activity has been reported. Detailed understanding of their molecular biology, enzymology, and structural biology are critically important, but the lack of a standardized residue numbering scheme and inconsistent secondary structure annotation has made comparative analyses sometimes difficult and cumbersome. Compounding this, in the post-AlphaFold world where we currently find ourselves, an extraordinary wealth of detailed structural information on these enzymes is literally at our fingertips; therefore it is vitally important that a standard numbering system is in place to facilitate the accurate and straightforward analysis of their structures. Here we present a residue numbering and secondary structure scheme for the class D enzymes based on the sequence and structure of OXA-48 and apply it to test targets to demonstrate the ease with which it can be used.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"11 4","pages":"805–812 805–812"},"PeriodicalIF":4.0,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143818917","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":"Role of RNA G-Quadruplexes in the Japanese Encephalitis Virus Genome and Their Recognition as Prospective Antiviral Targets.","authors":"Aakriti Singh, Prativa Majee, Laxmi Mishra, Surendra Kumar Prajapat, Tarun Kumar Sharma, Manjula Kalia, Amit Kumar","doi":"10.1021/acsinfecdis.4c00507","DOIUrl":"10.1021/acsinfecdis.4c00507","url":null,"abstract":"<p><p>G-quadruplexes (GQs) have been primarily studied in the context of cancer and neurodegenerative pathologies. However, recent research has shifted focus to their existence and functional roles in viral genomes, revealing GQ-regulated key pathways in various human pathogenic viruses. While GQ structures have been reported in the genomes of emerging and re-emerging viruses, RNA viruses have been understudied compared to DNA viruses, including notable examples such as human immunodeficiency virus-1, hepatitis C virus, Ebola virus, Nipah virus, Zika virus, and SARS-CoV-2. The flavivirus family, comprising the Japanese encephalitis virus (JEV), poses a significant global threat due to recurring outbreaks yet lacks approved antivirals. In this study, we identified and characterized eight putative G-quadruplex-forming motifs within essential genes involved in genome replication, assembly, and internalization in the host cell, conserved across different JEV isolates. The formation and stability of these motifs were validated through a multitude of biophysical and cell-based assays. The interaction and binding affinity of these motifs with the known GQ-binding ligand BRACO-19 were supported by biophysical assays, confirming the capability of these motifs to form GQ structures. Notably, BRACO-19 also exerted antiviral properties through reduction of viral replication and infectious virus titers as well as inhibition of viral protein expression, as evaluated by the cell-based assays. This comprehensive molecular characterization of G-quadruplex structures within the JEV genome highlights their potential as promising antiviral targets for intervention strategies against JEV infection through GQ-specific ligands.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":"558-572"},"PeriodicalIF":4.0,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142453224","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}
ACS Infectious DiseasesPub Date : 2025-03-14DOI: 10.1021/acsinfecdis.5c0003710.1021/acsinfecdis.5c00037
Wenxin Xu, Shuangchun Liu, Wanqian Li, Bin Xu, Ting Shan, Ronghai Lin*, Yun-Ting Du* and Guang Chen*,
{"title":"Plasmodium Infection Modulates Host Inflammatory Response through circRNAs during the Intracellular Stage in Red Blood Cells","authors":"Wenxin Xu, Shuangchun Liu, Wanqian Li, Bin Xu, Ting Shan, Ronghai Lin*, Yun-Ting Du* and Guang Chen*, ","doi":"10.1021/acsinfecdis.5c0003710.1021/acsinfecdis.5c00037","DOIUrl":"https://doi.org/10.1021/acsinfecdis.5c00037https://doi.org/10.1021/acsinfecdis.5c00037","url":null,"abstract":"<p >The integration of RNA- and DNA-based assays enables the investigation of disease dynamics, specifically assessing the role of asymptomatic or subclinical infections in malaria transmission. Circular RNAs (circRNAs), a distinct category of noncoding RNAs, are implicated in numerous pathogenic mechanisms. As of now, research has yet to explore circRNAs’ function in malaria infection. The findings revealed that <i>Plasmodium</i> infection upregulated 60 circRNAs and downregulated 71 in BALB/c mice. We selected 11 differentially expressed (DE) circRNAs according to function prediction of target miRNA-mRNA and coding protein, and these were further confirmed by validation experiments. IRESfinder, GO, and KEGG evaluations indicated that 7 DE circRNAs possess protein-coding potential and are enriched in the MAPK signaling cascade. In <i>P.y</i>17XL-infected BALB/c mouse models, the findings substantiated that the dynamic characteristics of DE circRNAs correlated with inflammation, and the MAPK and NF-κB signaling cascades were activated, also contributing to the inflammatory reaction during malaria infection. This study establishes <i>Plasmodium</i>-induced circRNA expression as a novel mechanism by which the parasite modulates host immune signaling, advancing the understanding of <i>Plasmodium–</i>host cell interactions. In addition, 42 circRNAs were found in normal BALB/c mice, and 25 circRNAs were discovered in <i>P.y</i>17XL-infected BALB/c mice, excluding 1238 circRNAs shared by normal and <i>P.y</i>17XL-infected BALB/c mice. <i>Plasmodium</i> infection changes the expression profile of circRNAs in the host, and these altered circRNAs are involved in the inflammatory response during malaria infection. In addition, <i>Plasmodium</i> possibly regulates the reverse splicing of pre-mRNA or m6A modification of RNA, inducing the production of novel circRNAs in the host.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"11 4","pages":"1018–1029 1018–1029"},"PeriodicalIF":4.0,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsinfecdis.5c00037","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143814731","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}
ACS Infectious DiseasesPub Date : 2025-03-14Epub Date: 2025-02-25DOI: 10.1021/acsinfecdis.4c00713
Raymonde B Bekale, Retsepile E Maphasa, Sarah D'Souza, Nai Jen Hsu, Avril Walters, Naomi Okugbeni, Craig Kinnear, Muazzam Jacobs, Samantha L Sampson, Mervin Meyer, Gene D Morse, Admire Dube
{"title":"Immunomodulatory Nanoparticles Induce Autophagy in Macrophages and Reduce <i>Mycobacterium tuberculosis</i> Burden in the Lungs of Mice.","authors":"Raymonde B Bekale, Retsepile E Maphasa, Sarah D'Souza, Nai Jen Hsu, Avril Walters, Naomi Okugbeni, Craig Kinnear, Muazzam Jacobs, Samantha L Sampson, Mervin Meyer, Gene D Morse, Admire Dube","doi":"10.1021/acsinfecdis.4c00713","DOIUrl":"10.1021/acsinfecdis.4c00713","url":null,"abstract":"<p><p>Tuberculosis (TB) is the leading cause of death from infectious disease. Macrophages are the primary immune responders and become the primary host cells for the causative agent <i>Mycobacterium tuberculosis</i>. Following the uptake of <i>M. tuberculosis</i>, the inherent antimicrobial action of macrophages is dampened, enabling the bacterium to reside within these cells and multiply. Rising resistance of <i>M. tuberculosis</i> to antibiotics has led to the investigation of novel approaches for the treatment of TB. Here, we report a host-directed approach, employing biomimetic Curdlan poly(lactic-<i>co</i>-glycolic acid) (C-PLGA) nanoparticles (NPs), and examine autophagy induction in infected macrophages, eradication of <i>M. tuberculosis</i> and immune modulation in a mouse model. We demonstrate that the NPs induce autophagy in <i>M. tuberculosis</i>-infected macrophages. Treatment of H37Rv infected C57BL/6 mice with these NPs reduced <i>M. tuberculosis</i> burden in the lungs of mice and modulated cytokines and chemokines and this work demonstrates that these immunomodulatory NPs are a potential treatment approach for TB.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":"610-625"},"PeriodicalIF":4.0,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11915374/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143490274","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}
ACS Infectious DiseasesPub Date : 2025-03-14Epub Date: 2025-02-27DOI: 10.1021/acsinfecdis.4c00835
William S Lawrence, Jennifer E Peel, Rosan de Winter, Losee L Ling, Anthony G Nitti, Aaron J Peoples, Rhythm Shukla, Harold D MacGillavry, Henry S Heine, Martha E Hensel, Elbert B Whorton, Markus Weingarth, Kim Lewis, Dallas E Hughes
{"title":"Teixobactin: A Resistance-Evading Antibiotic for Treating Anthrax.","authors":"William S Lawrence, Jennifer E Peel, Rosan de Winter, Losee L Ling, Anthony G Nitti, Aaron J Peoples, Rhythm Shukla, Harold D MacGillavry, Henry S Heine, Martha E Hensel, Elbert B Whorton, Markus Weingarth, Kim Lewis, Dallas E Hughes","doi":"10.1021/acsinfecdis.4c00835","DOIUrl":"10.1021/acsinfecdis.4c00835","url":null,"abstract":"<p><p>The antimicrobial resistance (AMR) crisis has been associated with millions of deaths. Of particular concern is the threat of bioweapons, exemplified by anthrax. Introduction of novel antibiotics helps mitigate AMR, but does not address the threat of bioweapons with engineered resistance. We reasoned that teixobactin, an antibiotic with no detectable resistance, is uniquely suited to address the challenge of weaponized anthrax. Teixobactin binds to immutable targets, precursors of cell wall polymers. Here we show that teixobactin is highly efficacious in a rabbit model of inhalation anthrax. Inhaling spores of <i>Bacillus anthracis</i> causes overwhelming morbidity and mortality. Treating rabbits with teixobactin after the onset of disease rapidly eliminates the pathogen from blood and tissues, normalizes body temperature, and prevents tissue damage. Teixobactin assembles into an irreversible supramolecular structure on the surface of <i>B. anthracis</i> membrane, likely contributing to its unusually high potency against anthrax. Antibiotics evading resistance provide a rational solution to both AMR and engineered bioweapons.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":"727-737"},"PeriodicalIF":4.0,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143513991","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}
ACS Infectious DiseasesPub Date : 2025-03-14Epub Date: 2025-02-27DOI: 10.1021/acsinfecdis.4c00808
Simon R Green, Justin R Harrison, Stephen Thompson, Dinakaran Murugesan, M Daben J Libardo, Curtis A Engelhart, Jaclynn Meshanni, Daniel Fletcher, Paul Scullion, Darren Edwards, Ola Epemolu, Nicole Mutter, Yoko Shishikura, Jennifer Riley, Thomas R Ioerger, Jose Juan Roca Guillén, Laura Guijarro López, Kevin D Read, Clifton E Barry, Dirk Schnappinger, Paul G Wyatt, Helena I M Boshoff, Laura A T Cleghorn
{"title":"Identification of a Series Containing a Pentafluorophenyl Moiety That Targets Pks13 to Inhibit Growth of <i>Mycobacterium tuberculosis</i>.","authors":"Simon R Green, Justin R Harrison, Stephen Thompson, Dinakaran Murugesan, M Daben J Libardo, Curtis A Engelhart, Jaclynn Meshanni, Daniel Fletcher, Paul Scullion, Darren Edwards, Ola Epemolu, Nicole Mutter, Yoko Shishikura, Jennifer Riley, Thomas R Ioerger, Jose Juan Roca Guillén, Laura Guijarro López, Kevin D Read, Clifton E Barry, Dirk Schnappinger, Paul G Wyatt, Helena I M Boshoff, Laura A T Cleghorn","doi":"10.1021/acsinfecdis.4c00808","DOIUrl":"10.1021/acsinfecdis.4c00808","url":null,"abstract":"<p><p>Although not currently in the infectious disease spotlight, there is still a pressing need for new agents to treat tuberculosis caused by <i>Mycobacterium tuberculosis</i>. As there is an ever-increasing amount of clinical resistance to the current drugs, ideally new drugs would be found against novel targets to circumvent pre-existing resistance. A phenotypic growth screen identified a novel singleton, <b>1</b>, as an inhibitor of <i>M. tuberculosis</i> growth. Mechanism-of-action studies determined that <b>1</b> targeted Pks13, an essential enzyme in cell wall biosynthesis that, as of yet, has not been targeted by agents in the clinic. The reactive nature of the pentafluorophenyl warhead meant that the molecule was inherently metabolically unstable. A medicinal chemistry optimization program is described that resulted in the identification of a compound that was reactive enough to still inhibit Pks13 and <i>M. tuberculosis</i> growth while being metabolically stable enough to explore in vivo.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":"715-726"},"PeriodicalIF":4.0,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11915372/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522189","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}