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      Towards the sustainable discovery and development of new antibiotics

      review-article
      1 , 2 , 3 , 4 , 2 , 5 , 6 , 7 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 2 , 17 , 18 , 18 , 19 , 20 , 21 , 22 , 2 , 23 , 2 , 23 , 2 , 24 , 25 , 1 , 2 , 1 , 2 , 1 , 1 , 1 , 2 , 1 , 2 , 2 , 2 , 2 , 26 , 2 , 27 , 2 , 27 , 2 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , , 1 , 2 ,
      Nature Reviews. Chemistry
      Nature Publishing Group UK
      Drug therapy, Business strategy in drug development

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          Abstract

          An ever-increasing demand for novel antimicrobials to treat life-threatening infections caused by the global spread of multidrug-resistant bacterial pathogens stands in stark contrast to the current level of investment in their development, particularly in the fields of natural-product-derived and synthetic small molecules. New agents displaying innovative chemistry and modes of action are desperately needed worldwide to tackle the public health menace posed by antimicrobial resistance. Here, our consortium presents a strategic blueprint to substantially improve our ability to discover and develop new antibiotics. We propose both short-term and long-term solutions to overcome the most urgent limitations in the various sectors of research and funding, aiming to bridge the gap between academic, industrial and political stakeholders, and to unite interdisciplinary expertise in order to efficiently fuel the translational pipeline for the benefit of future generations.

          Abstract

          Antimicrobial resistance is an increasing threat to public health and encouraging the development of new antimicrobials is one of the most important ways to address the problem. This Roadmap article aims to bring together industrial, academic and political partners, and proposes both short-term and long-term solutions to this challenge.

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          Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

          Summary Background Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. Methods In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. Findings 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p<0·0001), and d-dimer greater than 1 μg/mL (18·42, 2·64–128·55; p=0·0033) on admission. Median duration of viral shedding was 20·0 days (IQR 17·0–24·0) in survivors, but SARS-CoV-2 was detectable until death in non-survivors. The longest observed duration of viral shedding in survivors was 37 days. Interpretation The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. Funding Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.
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            Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance.

            Many different definitions for multidrug-resistant (MDR), extensively drug-resistant (XDR) and pandrug-resistant (PDR) bacteria are being used in the medical literature to characterize the different patterns of resistance found in healthcare-associated, antimicrobial-resistant bacteria. A group of international experts came together through a joint initiative by the European Centre for Disease Prevention and Control (ECDC) and the Centers for Disease Control and Prevention (CDC), to create a standardized international terminology with which to describe acquired resistance profiles in Staphylococcus aureus, Enterococcus spp., Enterobacteriaceae (other than Salmonella and Shigella), Pseudomonas aeruginosa and Acinetobacter spp., all bacteria often responsible for healthcare-associated infections and prone to multidrug resistance. Epidemiologically significant antimicrobial categories were constructed for each bacterium. Lists of antimicrobial categories proposed for antimicrobial susceptibility testing were created using documents and breakpoints from the Clinical Laboratory Standards Institute (CLSI), the European Committee on Antimicrobial Susceptibility Testing (EUCAST) and the United States Food and Drug Administration (FDA). MDR was defined as acquired non-susceptibility to at least one agent in three or more antimicrobial categories, XDR was defined as non-susceptibility to at least one agent in all but two or fewer antimicrobial categories (i.e. bacterial isolates remain susceptible to only one or two categories) and PDR was defined as non-susceptibility to all agents in all antimicrobial categories. To ensure correct application of these definitions, bacterial isolates should be tested against all or nearly all of the antimicrobial agents within the antimicrobial categories and selective reporting and suppression of results should be avoided. © 2011 European Society of Clinical Microbiology and Infectious Diseases. No claim to original US government works.
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              Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings

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                Author and article information

                Contributors
                heinz.moser@novartis.com
                rolf.mueller@helmholtz-hips.de
                Journal
                Nat Rev Chem
                Nat Rev Chem
                Nature Reviews. Chemistry
                Nature Publishing Group UK (London )
                2397-3358
                19 August 2021
                : 1-24
                Affiliations
                [1 ]GRID grid.11749.3a, ISNI 0000 0001 2167 7588, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) - Helmholtz Centre for Infection Research (HZI), and Department of Pharmacy, , Saarland University Campus E8.1, ; Saarbrücken, Germany
                [2 ]GRID grid.452463.2, German Center for Infection Research (DZIF), ; Braunschweig, Germany
                [3 ]GRID grid.10383.39, ISNI 0000 0004 1758 0937, Food and Drug Department, , University of Parma, ; Parma, Italy
                [4 ]GRID grid.5170.3, ISNI 0000 0001 2181 8870, The Novo Nordisk Foundation Center for Biosustainability, , Technical University of Denmark, ; Lyngby, Denmark
                [5 ]GRID grid.7490.a, ISNI 0000 0001 2238 295X, Department of Chemical Biology (CBIO), , Helmholtz Centre for Infection Research (HZI), ; Braunschweig, Germany
                [6 ]GRID grid.8664.c, ISNI 0000 0001 2165 8627, Infectious Diseases & Natural Product Research at EVOTEC, and Justus Liebig University Giessen, ; Giessen, Germany
                [7 ]Epigenetic Chemical Biology, Department of Structural Biology and Chemistry, Institut Pasteur, UMR n°3523, CNRS, Paris, France
                [8 ]GRID grid.428999.7, ISNI 0000 0001 2353 6535, Ecology and Evolution of Antibiotic Resistance Unit, , Microbiology Department, Institut Pasteur, CNRS UMR3525, ; Paris, France
                [9 ]GRID grid.29172.3f, ISNI 0000 0001 2194 6418, Université de Lorraine, INRAE, DynAMic, ; Nancy, France
                [10 ]GRID grid.7839.5, ISNI 0000 0004 1936 9721, Department of Biosciences, , Goethe University Frankfurt, ; Frankfurt, Germany
                [11 ]GRID grid.419554.8, ISNI 0000 0004 0491 8361, Max Planck Institute for Terrestrial Microbiology, Department of Natural Products in Organismic Interactions, ; Marburg, Germany
                [12 ]GRID grid.9983.b, ISNI 0000 0001 2181 4263, Faculty of Pharmacy, , University of Lisbon, ; Lisbon, Portugal
                [13 ]Unit MCAM, CNRS, National Museum of Natural History (MNHN), Paris, France
                [14 ]GRID grid.11749.3a, ISNI 0000 0001 2167 7588, Pharmaceutical Biotechnology, , Saarland University, ; Saarbrücken, Germany
                [15 ]GRID grid.4818.5, ISNI 0000 0001 0791 5666, Bioinformatics Group, , Wageningen University and Research, ; Wageningen, Netherlands
                [16 ]GRID grid.460789.4, ISNI 0000 0004 4910 6535, Institute for Integrative Biology of the Cell (I2BC) & Microbiology Department, , University of Paris-Saclay, ; Gif-sur-Yvette, France
                [17 ]GRID grid.7490.a, ISNI 0000 0001 2238 295X, Microbial Drugs (MWIS), Helmholtz Centre for Infection Research (HZI), ; Braunschweig, Germany
                [18 ]GRID grid.424782.f, ISNI 0000 0004 1778 9140, Fundación MEDINA, ; Granada, Spain
                [19 ]GRID grid.14830.3e, ISNI 0000 0001 2175 7246, Department of Molecular Microbiology, , John Innes Centre, ; Norwich, United Kingdom
                [20 ]GRID grid.29172.3f, ISNI 0000 0001 2194 6418, Molecular and Structural Enzymology Group, , Université de Lorraine, CNRS, IMoPA, ; Nancy, France
                [21 ]GRID grid.5379.8, ISNI 0000000121662407, Manchester Institute of Biotechnology, Department of Chemistry, School of Natural Sciences, , Faculty of Science and Engineering, University of Manchester, ; Manchester, United Kingdom
                [22 ]GRID grid.9027.c, ISNI 0000 0004 1757 3630, Department of Pharmaceutical Sciences, , University of Perugia, ; Perugia, Italy
                [23 ]GRID grid.10392.39, ISNI 0000 0001 2190 1447, Department of Microbial Bioactive Compounds, Interfaculty Institute of Microbiology and Infection Medicine, , University of Tübingen, ; Tübingen, Germany
                [24 ]GRID grid.10392.39, ISNI 0000 0001 2190 1447, Department of Microbiology/Biotechnology, Interfaculty Institute of Microbiology and Infection Medicine, , University of Tübingen, ; Tübingen, Germany
                [25 ]GRID grid.11843.3f, ISNI 0000 0001 2157 9291, Institute for Chemistry UMR 7177, , University of Strasbourg/CNRS, ITI InnoVec, ; Strasbourg, France
                [26 ]GRID grid.15078.3b, ISNI 0000 0000 9397 8745, Life Sciences & Chemistry, , Jacobs University Bremen, ; Bremen, Germany
                [27 ]GRID grid.15090.3d, ISNI 0000 0000 8786 803X, Institute of Medical Microbiology, Immunology and Parasitology (IMMIP), , University Hospital Bonn, ; Bonn, Germany
                [28 ]Biophys Ltd., Usk, Monmouthshire, United Kingdom
                [29 ]GRID grid.5337.2, ISNI 0000 0004 1936 7603, School of Law, , University of Bristol, ; Bristol, United Kingdom
                [30 ]GRID grid.505135.7, Recursion Pharmaceuticals, ; Salt Lake City, UT USA
                [31 ]Drug Discovery/Medicinal Chemistry, HiberCell, New York, NY USA
                [32 ]GRID grid.8993.b, ISNI 0000 0004 1936 9457, Department of Medicinal Chemistry, , Uppsala University, ; Uppsala, Sweden
                [33 ]AMR Insights, Amsterdam, Netherlands
                [34 ]GRID grid.8954.0, ISNI 0000 0001 0721 6013, Department of Food Science and Technology, Biotechnical Faculty, , University of Ljubljana, ; Ljubljana, Slovenia
                [35 ]GRID grid.11749.3a, ISNI 0000 0001 2167 7588, Chair for Clinical Bioinformatics, , Saarland University, University Hospital, ; Saarbrücken, Germany
                [36 ]BEAM Alliance, Paris, France
                [37 ]NAICONS Srl, Milan, Italy
                [38 ]GRID grid.428391.5, ISNI 0000 0004 0618 1092, Drugs for Neglected Diseases initiative (DNDi), ; Geneva, Switzerland
                [39 ]GRID grid.509622.a, The Global Antibiotic Research and Development Partnership (GARDP), ; Geneva, Switzerland
                [40 ]GRID grid.8241.f, ISNI 0000 0004 0397 2876, Division of Biological Chemistry and Drug Discovery, , University of Dundee, ; Dundee, United Kingdom
                [41 ]GRID grid.418424.f, ISNI 0000 0004 0439 2056, Novartis Institutes for BioMedical Research (NIBR), ; Emeryville, CA USA
                Author information
                http://orcid.org/0000-0002-8260-5120
                http://orcid.org/0000-0001-5266-5926
                http://orcid.org/0000-0001-6048-5909
                http://orcid.org/0000-0002-2191-2821
                http://orcid.org/0000-0002-6129-7093
                http://orcid.org/0000-0001-5453-7485
                http://orcid.org/0000-0002-3012-2960
                http://orcid.org/0000-0002-6791-3256
                http://orcid.org/0000-0003-0971-3536
                http://orcid.org/0000-0002-2615-1574
                http://orcid.org/0000-0001-7408-5084
                http://orcid.org/0000-0002-1604-3318
                http://orcid.org/0000-0002-9823-2090
                http://orcid.org/0000-0003-3096-2465
                http://orcid.org/0000-0003-0818-2614
                http://orcid.org/0000-0002-5361-0895
                http://orcid.org/0000-0003-1460-473X
                http://orcid.org/0000-0002-5238-1314
                http://orcid.org/0000-0002-8013-2139
                http://orcid.org/0000-0002-1042-5665
                Article
                313
                10.1038/s41570-021-00313-1
                8374425
                34426795
                10db832c-8611-47ba-8737-630602a16a5c
                © Springer Nature Limited 2021

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

                History
                : 1 July 2021
                Categories
                Roadmap

                drug therapy,business strategy in drug development

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