Many Faces: The Global Landscape of Medicinal Chemistry

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Learn More CiteCitationCitation and abstractCitation and referencesMore citation options ShareShare onFacebookX (Twitter)WeChatLinkedInRedditEmailJump toExpandCollapse EditorialFebruary 12, 2025Many Faces: The Global Landscape of Medicinal ChemistryClick to copy article linkArticle link copied!Lori Ferrins*Lori FerrinsPharmaceutical Sciences, Northeastern University, Boston, Massachusetts 02115, United StatesChemistry and Chemical Biology, Northeastern University, Boston, Massachusetts 02115, United States*[email protected]More by Lori Ferrinshttps://orcid.org/0000-0001-8992-0919Ashley AdamsAshley AdamsRecursion Pharmaceuticals Inc., Salt Lake City, Utah 84101, United StatesMore by Ashley Adamshttps://orcid.org/0000-0003-0823-3709Anna Junker*Anna JunkerDepartment of Preclinical Imaging and Radiopharmacy, University of Tübingen, Tuebingen 72076, Germany*[email protected]More by Anna Junkerhttps://orcid.org/0000-0001-5151-0930Open PDFACS Medicinal Chemistry LettersCite this: ACS Med. Chem. Lett. 2025, XXXX, XXX, XXX-XXXClick to copy citationCitation copied!https://pubs.acs.org/doi/10.1021/acsmedchemlett.5c00041https://doi.org/10.1021/acsmedchemlett.5c00041Published February 12, 2025 Publication History Received 22 January 2025Published online 12 February 2025editorialPublished 2025 by American Chemical Society. This publication is available under these Terms of Use. Request reuse permissionsThis publication is licensed for personal use by The American Chemical Society. ACS PublicationsPublished 2025 by American Chemical SocietyIn the Call for Papers for this Special Issue, published jointly by the Journal of Medicinal Chemistry and ACS Medicinal Chemistry Letters, we recognized the 2022 report from the American Chemical Society analyzing the demographics of the ACS Publications community, with a specific focus on the location of the corresponding authors' affiliations. With the recent release of the 2024 Diversity Data Report, (1) we want to highlight the location of corresponding authors in published manuscripts across the biological and medicinal chemistry field: 34% (32% in 2022) of publications come from groups in East Asia and the Pacific, 33% (31% in 2022) from the United States and Canada, 21% (21% in 2022) from Europe and Central Asia, and 5% (8% in 2022) from South Asia. Our goal with this Special Issue was to celebrate the contributions to the medicinal chemistry field from across the globe, and we were pleased to receive contributions from every major continent (Figure 1).The articles in this Special Issue cover many of the topics and subfields that are becoming increasingly prevalent in the quest for novel therapeutics and modalities.From large pharmaceutical companies, there are key disclosures of tool compounds and candidates: BI-9508 from Boehringer Ingelheim (Germany), JNJ-1802 from Janssen (Belgium), and I-BET787 from GSK (United Kingdom). Further disclosures from biotech are also highlighted, specifically GUB021794 from Gubra (Denmark) and ACT-1016 from Idorsia (Switzerland). There are also contributions from early discovery teams showcasing ligandability assessments such as those performed by the Novartis team (Switzerland); a fragment-based drug discovery campaign that delivered pharmacological chaperones of GCase from Astex (United Kingdom); the optimization of a DEL-derived macrocycle hit from Symeres (The Netherlands) using combinatorial array chemistry; the development of MicroCycle, a platform that incorporates microscale chemistry, automated purification, and in situ quantification to provide assay-ready plates of high-quality chemical matter from Novartis Biomedical Research (USA and Switzerland); and the development of MAT2a inhibitors from fragment screening data from AstraZeneca (United Kingdom and USA). We also have a timely Editorial on drug discovery by pharmaceutical companies in India and China, highlighting that there is value in collaboration between industry and academia.Figure 1Figure 1. Geographical distribution of corresponding authors of manuscripts included in this Special Issue.High Resolution ImageDownload MS PowerPoint SlideThe diversity of targets being explored by researchers highlights the breadth of innovation in therapeutic discovery. Advances include the development of 7-ethynyl pyrazolo[3,4-d]pyrimidine ribosides, leading to a novel tricyclic nucleoside, from researchers in Belgium and the USA, and the structural tuning of c-KIT 1 G-quadruplexes for precise targeting by researchers in India. Chinese researchers have also identified NLRP3 inhibitors that disrupt its interaction with NEK7 by targeting the LRR domain, offering promise for treating rheumatoid arthritis, and another team from China identified a series of small molecules derived from PPTN that emerged as potent P2Y14 receptor antagonists to address inflammatory bowel disease. Finally, covalent modulation of targets continues to see increased research efforts, with researchers from Germany exploring covalent modulation of cathepsin S to refine approaches for targeted protease inhibition. These efforts underscore the expanding landscape of molecular targets across diverse disease areas.Global interest in cancer research is reflected in this Special Issue, with contributions from collaborative teams worldwide. A South Africa–USA consortium focused on improving the aqueous solubility of rigidin-inspired 7-deazahypoxanthines, synthesizing derivatives that retained potent antiproliferative activity and demonstrated disruption of microtubulin dynamics and spindle morphology. Meanwhile, researchers from Turkey, Japan, and Australia developed selenosemicarbazones as potent anticancer agents through an interesting isosteric replacement of sulfur with selenium.The field of molecular imaging is seeing exciting advancements in the development of new radiotracers and imaging strategies aimed at improving diagnosis. For example, advancements in positron emission tomography (PET) imaging are pushing boundaries in neuroscience, and there is a comprehensive Perspective on the latest developments in the area from a team of researchers that spanned the USA and China, highlighting advancements in the development of radioligands for mGluR4. A team from China took this further by developing an 18F-labeled amino acid tracer, and new developments in chemistry that enabled their efficient synthesis are reported. Researchers in Germany report the synthesis of an 18F-labeled radiotracer for interleukin-8 receptor beta (CXCR2), which they note is a target of interest for imaging in inflammatory diseases. Finally, a team from Korea reports improvements in the radioiodination of proteins and antibodies.Research continues into SARS-CoV-2 advances, with the identification of Mac1 as a novel antiviral target to suppress viral replication from a Finnish-led team and the application of amphiphilic heparinoids by a team comprising researchers from Australia, India, and Israel. Complementing these studies are a Perspective piece that reviews the progress in designing protein–protein interaction inhibitors targeting a range of viral pathogens, including HIV, SARS-CoV-2, HCV, Ebola, Dengue, and Chikungunya viruses, and a Technical Note on the use of conjugated nonionic detergent micelles as purification platforms for human IgA1-IgA2 dimers. Parasitic diseases are also addressed, including a study tackling the cardiotoxicity of the antimalarial drug astemizole linked to hERG liabilities, aiming to improve its therapeutic safety profile, by a team of South African researchers, and the development of nitrotriazoles as promising treatments for neglected tropical diseases like Chagas disease and leishmaniasis from a team in Brazil.Antibiotic resistance has been identified as a top global public health threat. (2) To address this, a collaborative team of researchers from Argentina, Uruguay, Colombia, the USA, and the U.K. explored the bisthiazolidine (BTZ) scaffold to find potent broad-spectrum metallo-β-lactamase inhibitors which enhance carbapenem efficacy and represent a promising advance in combating antimicrobial resistance. A research team from Germany has advanced the development of selective peptide deformylase inhibitors, identifying a novel scaffold and an alternative conformation that could serve as a foundation for optimizing bacterial specificity. Together, these articles underscore innovative and collaborative efforts to address diverse global health concerns.Continued efforts in the development of kinase inhibitors demonstrate their potential across diverse therapeutic areas. Research into PI3Kδ selective inhibitors for asthma by a team of researchers in Italy from Aptuit, an Evotec company, and Chiesi Farmaceutici S.p.A., revealed appropriate vectors to optimize ADME properties and PI3K selectivity, paving the way for targeted treatments. Taiwanese researchers report that dual MER/AXL kinase inhibitors have emerged as bifunctional small molecules capable of modulating the tumor microenvironment. Meanwhile, the design of conformationally constrained ALK2 inhibitors from Canadian researchers holds promise for treating diffuse intrinsic pontine glioma, a rare and aggressive pediatric brain tumor. Collectively, these advancements underscore the versatility and clinical relevance of kinase inhibitors in addressing complex diseases while highlighting the challenges in achieving broad kinome selectivity.The continued exploration of proteolysis-targeting chimeras (PROTACs) highlights their potential as versatile tools in targeted therapy. A USA-based team has developed galactose-based prodrugs that selectively degrade senescent cancer cell proteins, demonstrating enhanced senolytic efficacy and significant tumor growth inhibition in vivo when combined with etoposide. Meanwhile, researchers in India have focused on the molecular mechanisms underpinning PROTAC efficacy, investigating the dynamics of ternary complex formation involving various E3 ligases (VHL, CRBN, and cIAP) and target proteins. Their findings on linker length, cooperativity, and structural stability offer insights for designing PROTACs with improved selectivity and therapeutic potential across disease areas.Medicinal chemistry efforts targeting central nervous system diseases are advancing with innovative approaches to tackle complex neurological disorders. A U.K. team identified a synthetic single-domain antibody, αSP1, which specifically inhibits the amyloid formation of α-synuclein, a key protein implicated in Parkinson's disease, through its precise binding to the P1 region. Given its small size, the researchers postulate that it could have improved blood–brain barrier permeability. A team from Spain and India demonstrates the potential of Raltitrexed as a potential repurposing therapy for Alzheimer's disease, showing its efficacy in reducing Aβ aggregates. An Italian team has employed computational and experimental methods to discover novel KCNT1 channel blockers, including CPK18 and 20, in their efforts to identify novel treatments for severe drug-resistant epilepsy caused by KCNT1 gain-of-function variants.The landscape of medicinal chemistry continues to expand with the exploration of new molecular entities and unconventional chemical frameworks. A Perspective on the use of metallacarboranes highlights their potential as innovative building blocks due to their metabolic stability and versatility, offering novel therapeutic applications across various diseases. Additionally, the concept of "natural selection" in successful small molecule drug discovery, as discussed by a U.K.-based team, points out the importance of natural product fragments in iterative optimization processes for enhancing the physicochemical properties and efficacy of lead compounds, serving as a guiding principle in modern drug development.This timely Special Issue focuses on the breadth of medicinal chemistry globally, originating in academic and industrial laboratories, to provide a snapshot of the united effort to deliver advancements that benefit human health. As Louis Pasteur aptly said, "Science knows no country, because knowledge belongs to humanity, and is the torch which illuminates the world." This sentiment underscores the collaborative nature of scientific progress, where breakthroughs in medicinal chemistry transcend borders, advancing our collective understanding and improving lives worldwide.Author InformationClick to copy section linkSection link copied!Corresponding AuthorsLori Ferrins, Associate Editor, Journal of Medicinal Chemistry, Pharmaceutical Sciences, Northeastern University, Boston, Massachusetts 02115, United States; Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts 02115, United States, https://orcid.org/0000-0001-8992-0919, Email: [email protected]Anna Junker, Topic Editor, ACS Medicinal Chemistry Letters, Department of Preclinical Imaging and Radiopharmacy, University of Tübingen, Tuebingen 72076, Germany, https://orcid.org/0000-0001-5151-0930, Email: [email protected]AuthorAshley Adams, Guest Editor, ACS Medicinal Chemistry Letters, Recursion Pharmaceuticals Inc., Salt Lake City, Utah 84101, United States, https://orcid.org/0000-0003-0823-3709NotesViews expressed in this editorial are those of the authors and not necessarily the views of the ACS.ReferencesClick to copy section linkSection link copied! This article references 2 other publications. 1ACS Publications, Diversity Data Report 2024. American Chemical Society, https://pubsdiversity.acs.org/data/2024/index.htmlGoogle ScholarThere is no corresponding record for this reference.2Murray, C. J. L.; Ikuta, K. S.; Sharara, F.; Swetschinski, L.; Robles Aguilar, G.; Gray, A.; Han, C.; Bisignano, C.; Rao, P.; Wool, E.; Johnson, S. C.; Browne, A. J.; Chipeta, M. G.; Fell, F.; Hackett, S.; Haines-Woodhouse, G.; Kashef Hamadani, B. H.; Kumaran, E. A. P.; McManigal, B.; Achalapong, S.; Agarwal, R.; Akech, S.; Albertson, S.; Amuasi, J.; Andrews, J.; Aravkin, A.; Ashley, E.; Babin, F.-X.; Bailey, F.; Baker, S.; Basnyat, B.; Bekker, A.; Bender, R.; Berkley, J. A.; Bethou, A.; Bielicki, J.; Boonkasidecha, S.; Bukosia, J.; Carvalheiro, C.; Castañeda-Orjuela, C.; Chansamouth, V.; Chaurasia, S.; Chiurchiù, S.; Chowdhury, F.; Clotaire Donatien, R.; Cook, A. J.; Cooper, B.; Cressey, T. R.; Criollo-Mora, E.; Cunningham, M.; Darboe, S.; Day, N. P. J.; De Luca, M.; Dokova, K.; Dramowski, A.; Dunachie, S. J.; Duong Bich, T.; Eckmanns, T.; Eibach, D.; Emami, A.; Feasey, N.; Fisher-Pearson, N.; Forrest, K.; Garcia, C.; Garrett, D.; Gastmeier, P.; Giref, A. Z.; Greer, R. C.; Gupta, V.; Haller, S.; Haselbeck, A.; Hay, S. I.; Holm, M.; Hopkins, S.; Hsia, Y.; Iregbu, K. C.; Jacobs, J.; Jarovsky, D.; Javanmardi, F.; Jenney, A. W. J.; Khorana, M.; Khusuwan, S.; Kissoon, N.; Kobeissi, E.; Kostyanev, T.; Krapp, F.; Krumkamp, R.; Kumar, A.; Kyu, H. H.; Lim, C.; Lim, K.; Limmathurotsakul, D.; Loftus, M. J.; Lunn, M.; Ma, J.; Manoharan, A.; Marks, F.; May, J.; Mayxay, M.; Mturi, N.; Munera-Huertas, T.; Musicha, P.; Musila, L. A.; Mussi-Pinhata, M. M.; Naidu, R. N.; Nakamura, T.; Nanavati, R.; Nangia, S.; Newton, P.; Ngoun, C.; Novotney, A.; Nwakanma, D.; Obiero, C. W.; Ochoa, T. J.; Olivas-Martinez, A.; Olliaro, P.; Ooko, E.; Ortiz-Brizuela, E.; Ounchanum, P.; Pak, G. D.; Paredes, J. L.; Peleg, A. Y.; Perrone, C.; Phe, T.; Phommasone, K.; Plakkal, N.; Ponce-de-Leon, A.; Raad, M.; Ramdin, T.; Rattanavong, S.; Riddell, A.; Roberts, T.; Robotham, J. V.; Roca, A.; Rosenthal, V. D.; Rudd, K. E.; Russell, N.; Sader, H. S.; Saengchan, W.; Schnall, J.; Scott, J. A. G.; Seekaew, S.; Sharland, M.; Shivamallappa, M.; Sifuentes-Osornio, J.; Simpson, A. J.; Steenkeste, N.; Stewardson, A. J.; Stoeva, T.; Tasak, N.; Thaiprakong, A.; Thwaites, G.; Tigoi, C.; Turner, C.; Turner, P.; van Doorn, H. R.; Velaphi, S.; Vongpradith, A.; Vongsouvath, M.; Vu, H.; Walsh, T.; Walson, J. L.; Waner, S.; Wangrangsimakul, T.; Wannapinij, P.; Wozniak, T.; Young Sharma, T. E. M. W.; Yu, K. C.; Zheng, P.; Sartorius, B.; Lopez, A. D.; Stergachis, A.; Moore, C.; Dolecek, C.; Naghavi, M. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet 2022, 399 (10325), 629– 655, DOI: 10.1016/S0140-6736(21)02724-0 Google Scholar2Global burden of bacterial antimicrobial resistance in 2019: a systematic analysisMurray, Christopher J. L.; Ikuta, Kevin Shunji; Sharara, Fablina; Swetschinski, Lucien; Aguilar, Gisela Robles; Gray, Authia; Han, Chieh; Bisignano, Catherine; Rao, Puja; Wool, Eve; et al.Lancet (2022), 399 (10325), 629-655CODEN: LANCAO; ISSN:0140-6736. (Elsevier Ltd.) Antimicrobial resistance (AMR) poses a major threat to human health around the world. Previous publications have estd. the effect of AMR on incidence, deaths, hospital length of stay, and health-care costs for specific pathogen-drug combinations in select locations. To our knowledge, this study presents the most comprehensive ests. of AMR burden to date. We estd. deaths and disability-adjusted life-years (DALYs) attributable to and assocd. with bacterial AMR for 23 pathogens and 88 pathogen-drug combinations in 204 countries and territories in 2019. We obtained data from systematic literature reviews, hospital systems, surveillance systems, and other sources, covering 471 million individual records or isolates and 7585 study-location-years. We used predictive statistical modeling to produce ests. of AMR burden for all locations, including for locations with no data. Our approach can be divided into five broad components: no. of deaths where infection played a role, proportion of infectious deaths attributable to a given infectious syndrome, proportion of infectious syndrome deaths attributable to a given pathogen, the percentage of a given pathogen resistant to an antibiotic of interest, and the excess risk of death or duration of an infection assocd. with this resistance. Using these components, we estd. disease burden based on two counterfactuals: deaths attributable to AMR (based on an alternative scenario in which all drug-resistant infections were replaced by drug-susceptible infections), and deaths assocd. with AMR (based on an alternative scenario in which all drug-resistant infections were replaced by no infection). We generated 95% uncertainty intervals (UIs) for final ests. as the 25th and 975th ordered values across 1000 posterior draws, and models were cross-validated for out-of-sample predictive validity. We present final ests. aggregated to the global and regional level. On the basis of our predictive statistical models, there were an estd. 4.95 million (3.62-6.57) deaths assocd. with bacterial AMR in 2019, including 1.27 million (95% UI 0.911-1.71) deaths attributable to bacterial AMR. At the regional level, we estd. the all-age death rate attributable to resistance to be highest in western sub-Saharan Africa, at 27.3 deaths per 100 000 (20.9-35.3), and lowest in Australasia, at 6.5 deaths (4.3-9.4) per 100 000. Lower respiratory infections accounted for more than 1.5 million deaths assocd. with resistance in 2019, making it the most burdensome infectious syndrome. The six leading pathogens for deaths assocd. with resistance (Escherichia coli, followed by Staphylococcus aureus, Klebsiella pneumoniae, Streptococcus pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa) were responsible for 929 000 (660 000-1 270 000) deaths attributable to AMR and 3.57 million (2.62-4.78) deaths assocd. with AMR in 2019. One pathogen-drug combination, meticillin-resistant S aureus, caused more than 100 000 deaths attributable to AMR in 2019, while six more each caused 50 000-100 000 deaths: multidrug-resistant excluding extensively drug-resistant tuberculosis, third-generation cephalosporin-resistant E coli, carbapenem-resistant A baumannii, fluoroquinolone-resistantE coli, carbapenem-resistant K pneumoniae, and third-generation cephalosporin-resistant K pneumoniae. To our knowledge, this study provides the first comprehensive assessment of the global burden of AMR, as well as an evaluation of the availability of data. AMR is a leading cause of death around the world, with the highest burdens in low-resource settings. Understanding the burden of AMR and the leading pathogen-drug combinations contributing to it is crucial to making informed and location-specific policy decisions, particularly about infection prevention and control programs, access to essential antibiotics, and research and development of new vaccines and antibiotics. There are serious data gaps in many low-income settings, emphasizing the need to expand microbiol. lab. capacity and data collection systems to improve our understanding of this important human health threat. >> More from SciFinder ®https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XpvFGrtb0%253D&md5=b99b0063434bbae5c4d799ab977e973cCited By Click to copy section linkSection link copied!This article has not yet been cited by other publications.Download PDFFiguresReferences Get e-AlertsGet e-AlertsACS Medicinal Chemistry LettersCite this: ACS Med. Chem. Lett. 2025, XXXX, XXX, XXX-XXXClick to copy citationCitation copied!https://doi.org/10.1021/acsmedchemlett.5c00041Published February 12, 2025 Publication History Received 22 January 2025Published online 12 February 2025Published 2025 by American Chemical Society. This publication is available under these Terms of Use. Request reuse permissionsArticle Views-Altmetric-Citations-Learn about these metrics closeArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated.Recommended Articles FiguresReferencesFigure 1Figure 1. Geographical distribution of corresponding authors of manuscripts included in this Special Issue.High Resolution ImageDownload MS PowerPoint SlideReferences This article references 2 other publications. 1ACS Publications, Diversity Data Report 2024. American Chemical Society, https://pubsdiversity.acs.org/data/2024/index.htmlThere is no corresponding record for this reference.2Murray, C. J. L.; Ikuta, K. S.; Sharara, F.; Swetschinski, L.; Robles Aguilar, G.; Gray, A.; Han, C.; Bisignano, C.; Rao, P.; Wool, E.; Johnson, S. C.; Browne, A. J.; Chipeta, M. G.; Fell, F.; Hackett, S.; Haines-Woodhouse, G.; Kashef Hamadani, B. H.; Kumaran, E. A. P.; McManigal, B.; Achalapong, S.; Agarwal, R.; Akech, S.; Albertson, S.; Amuasi, J.; Andrews, J.; Aravkin, A.; Ashley, E.; Babin, F.-X.; Bailey, F.; Baker, S.; Basnyat, B.; Bekker, A.; Bender, R.; Berkley, J. A.; Bethou, A.; Bielicki, J.; Boonkasidecha, S.; Bukosia, J.; Carvalheiro, C.; Castañeda-Orjuela, C.; Chansamouth, V.; Chaurasia, S.; Chiurchiù, S.; Chowdhury, F.; Clotaire Donatien, R.; Cook, A. J.; Cooper, B.; Cressey, T. R.; Criollo-Mora, E.; Cunningham, M.; Darboe, S.; Day, N. P. J.; De Luca, M.; Dokova, K.; Dramowski, A.; Dunachie, S. J.; Duong Bich, T.; Eckmanns, T.; Eibach, D.; Emami, A.; Feasey, N.; Fisher-Pearson, N.; Forrest, K.; Garcia, C.; Garrett, D.; Gastmeier, P.; Giref, A. Z.; Greer, R. C.; Gupta, V.; Haller, S.; Haselbeck, A.; Hay, S. I.; Holm, M.; Hopkins, S.; Hsia, Y.; Iregbu, K. C.; Jacobs, J.; Jarovsky, D.; Javanmardi, F.; Jenney, A. W. J.; Khorana, M.; Khusuwan, S.; Kissoon, N.; Kobeissi, E.; Kostyanev, T.; Krapp, F.; Krumkamp, R.; Kumar, A.; Kyu, H. H.; Lim, C.; Lim, K.; Limmathurotsakul, D.; Loftus, M. J.; Lunn, M.; Ma, J.; Manoharan, A.; Marks, F.; May, J.; Mayxay, M.; Mturi, N.; Munera-Huertas, T.; Musicha, P.; Musila, L. A.; Mussi-Pinhata, M. M.; Naidu, R. N.; Nakamura, T.; Nanavati, R.; Nangia, S.; Newton, P.; Ngoun, C.; Novotney, A.; Nwakanma, D.; Obiero, C. W.; Ochoa, T. J.; Olivas-Martinez, A.; Olliaro, P.; Ooko, E.; Ortiz-Brizuela, E.; Ounchanum, P.; Pak, G. D.; Paredes, J. L.; Peleg, A. Y.; Perrone, C.; Phe, T.; Phommasone, K.; Plakkal, N.; Ponce-de-Leon, A.; Raad, M.; Ramdin, T.; Rattanavong, S.; Riddell, A.; Roberts, T.; Robotham, J. V.; Roca, A.; Rosenthal, V. D.; Rudd, K. E.; Russell, N.; Sader, H. S.; Saengchan, W.; Schnall, J.; Scott, J. A. G.; Seekaew, S.; Sharland, M.; Shivamallappa, M.; Sifuentes-Osornio, J.; Simpson, A. J.; Steenkeste, N.; Stewardson, A. J.; Stoeva, T.; Tasak, N.; Thaiprakong, A.; Thwaites, G.; Tigoi, C.; Turner, C.; Turner, P.; van Doorn, H. R.; Velaphi, S.; Vongpradith, A.; Vongsouvath, M.; Vu, H.; Walsh, T.; Walson, J. L.; Waner, S.; Wangrangsimakul, T.; Wannapinij, P.; Wozniak, T.; Young Sharma, T. E. M. W.; Yu, K. C.; Zheng, P.; Sartorius, B.; Lopez, A. D.; Stergachis, A.; Moore, C.; Dolecek, C.; Naghavi, M. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet 2022, 399 (10325), 629– 655, DOI: 10.1016/S0140-6736(21)02724-0 2Global burden of bacterial antimicrobial resistance in 2019: a systematic analysisMurray, Christopher J. L.; Ikuta, Kevin Shunji; Sharara, Fablina; Swetschinski, Lucien; Aguilar, Gisela Robles; Gray, Authia; Han, Chieh; Bisignano, Catherine; Rao, Puja; Wool, Eve; et al.Lancet (2022), 399 (10325), 629-655CODEN: LANCAO; ISSN:0140-6736. (Elsevier Ltd.) Antimicrobial resistance (AMR) poses a major threat to human health around the world. Previous publications have estd. the effect of AMR on incidence, deaths, hospital length of stay, and health-care costs for specific pathogen-drug combinations in select locations. To our knowledge, this study presents the most comprehensive ests. of AMR burden to date. We estd. deaths and disability-adjusted life-years (DALYs) attributable to and assocd. with bacterial AMR for 23 pathogens and 88 pathogen-drug combinations in 204 countries and territories in 2019. We obtained data from systematic literature reviews, hospital systems, surveillance systems, and other sources, covering 471 million individual records or isolates and 7585 study-location-years. We used predictive statistical modeling to produce ests. of AMR burden for all locations, including for locations with no data. Our approach can be divided into five broad components: no. of deaths where infection played a role, proportion of infectious deaths attributable to a given infectious syndrome, proportion of infectious syndrome deaths attributable to a given pathogen, the percentage of a given pathogen resistant to an antibiotic of interest, and the excess risk of death or duration of an infection assocd. with this resistance. Using these components, we estd. disease burden based on two counterfactuals: deaths attributable to AMR (based on an alternative scenario in which all drug-resistant infections were replaced by drug-susceptible infections), and deaths assocd. with AMR (based on an alternative scenario in which all drug-resistant infections were replaced by no infection). We generated 95% uncertainty intervals (UIs) for final ests. as the 25th and 975th ordered values across 1000 posterior draws, and models were cross-validated for out-of-sample predictive validity. We present final ests. aggregated to the global and regional level. On the basis of our predictive statistical models, there were an estd. 4.95 million (3.62-6.57) deaths assocd. with bacterial AMR in 2019, including 1.27 million (95% UI 0.911-1.71) deaths attributable to bacterial AMR. At the regional level, we estd. the all-age death rate attributable to resistance to be highest in western sub-Saharan Africa, at 27.3 deaths per 100 000 (20.9-35.3), and lowest in Australasia, at 6.5 deaths (4.3-9.4) per 100 000. Lower respiratory infections accounted for more than 1.5 million deaths assocd. with resistance in 2019, making it the most burdensome infectious syndrome. The six leading pathogens for deaths assocd. with resistance (Escherichia coli, followed by Staphylococcus aureus, Klebsiella pneumoniae, Streptococcus pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa) were responsible for 929 000 (660 000-1 270 000) deaths attributable to AMR and 3.57 million (2.62-4.78) deaths assocd. with AMR in 2019. One pathogen-drug combination, meticillin-resistant S aureus, caused more than 100 000 deaths attributable to AMR in 2019, while six more each caused 50 000-100 000 deaths: multidrug-resistant excluding extensively drug-resistant tuberculosis, third-generation cephalosporin-resistant E coli, carbapenem-resistant A baumannii, fluoroquinolone-resistantE coli, carbapenem-resistant K pneumoniae, and third-generation cephalosporin-resistant K pneumoniae. To our knowledge, this study provides the first comprehensive assessment of the global burden of AMR, as well as an evaluation of the availability of data. AMR is a leading cause of death around the world, with the highest burdens in low-resource settings. Understanding the burden of AMR and the leading pathogen-drug combinations contributing to it is crucial to making informed and location-specific policy decisions, particularly about infection prevention and control programs, access to essential antibiotics, and research and development of new vaccines and antibiotics. There are serious data gaps in many low-income settings, emphasizing the need to expand microbiol. lab. capacity and data collection systems to improve our understanding of this important human health threat. >> More from SciFinder ®https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XpvFGrtb0%253D&md5=b99b0063434bbae5c4d799ab977e973c