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      Antibiotics in the clinical pipeline in October 2019

      review-article
      ,
      The Journal of Antibiotics
      Nature Publishing Group UK
      Drug development, Antimicrobials, Medicinal chemistry

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          Abstract

          The development of new and effective antibacterial drugs to treat multi-drug resistant (MDR) bacteria, especially Gram-negative (G−ve) pathogens, is acknowledged as one of the world’s most pressing health issues; however, the discovery and development of new, nontoxic antibacterials is not a straightforward scientific task, which is compounded by a challenging economic model. This review lists the antibacterials, β-lactamase/β-lactam inhibitor (BLI) combinations, and monoclonal antibodies (mAbs) first launched around the world since 2009 and details the seven new antibiotics and two new β-lactam/BLI combinations launched since 2016. The development status, mode of action, spectra of activity, lead source, and administration route for the 44 small molecule antibacterials, eight β-lactamase/BLI combinations, and one antibody drug conjugate (ADC) being evaluated in worldwide clinical trials at the end of October 2019 are described. Compounds discontinued from clinical development since 2016 and new antibacterial pharmacophores are also reviewed. There has been an increase in the number of early stage clinical candidates, which has been fueled by antibiotic-focused funding agencies; however, there is still a significant gap in the pipeline for the development of new antibacterials with activity against β-metallolactamases, orally administered with broad spectrum G−ve activity, and new treatments for MDR Acinetobacter and gonorrhea.

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          Drugs for bad bugs: confronting the challenges of antibacterial discovery.

          The sequencing of the first complete bacterial genome in 1995 heralded a new era of hope for antibacterial drug discoverers, who now had the tools to search entire genomes for new antibacterial targets. Several companies, including GlaxoSmithKline, moved back into the antibacterials area and embraced a genomics-derived, target-based approach to screen for new classes of drugs with novel modes of action. Here, we share our experience of evaluating more than 300 genes and 70 high-throughput screening campaigns over a period of 7 years, and look at what we learned and how that has influenced GlaxoSmithKline's antibacterials strategy going forward.
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            β-Lactamases and β-Lactamase Inhibitors in the 21st Century

            The β-lactams retain a central place in the antibacterial armamentarium. In Gram-negative bacteria, β-lactamase enzymes that hydrolyze the amide bond of the four-membered β-lactam ring are the primary resistance mechanism, with multiple enzymes disseminating on mobile genetic elements across opportunistic pathogens such as Enterobacteriaceae (e.g., Escherichia coli) and non-fermenting organisms (e.g., Pseudomonas aeruginosa). β-Lactamases divide into four classes; the active-site serine β-lactamases (classes A, C and D) and the zinc-dependent or metallo-β-lactamases (MBLs; class B). Here we review recent advances in mechanistic understanding of each class, focusing upon how growing numbers of crystal structures, in particular for β-lactam complexes, and methods such as neutron diffraction and molecular simulations, have improved understanding of the biochemistry of β-lactam breakdown. A second focus is β-lactamase interactions with carbapenems, as carbapenem-resistant bacteria are of grave clinical concern and carbapenem-hydrolyzing enzymes such as KPC (class A) NDM (class B) and OXA-48 (class D) are proliferating worldwide. An overview is provided of the changing landscape of β-lactamase inhibitors, exemplified by the introduction to the clinic of combinations of β-lactams with diazabicyclooctanone and cyclic boronate serine β-lactamase inhibitors, and of progress and strategies toward clinically useful MBL inhibitors. Despite the long history of β-lactamase research, we contend that issues including continuing unresolved questions around mechanism; opportunities afforded by new technologies such as serial femtosecond crystallography; the need for new inhibitors, particularly for MBLs; the likely impact of new β-lactam:inhibitor combinations and the continuing clinical importance of β-lactams mean that this remains a rewarding research area.
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              Bacterial Metabolism and Antibiotic Efficacy

              Summary Antibiotics target energy-consuming processes. As such, perturbations to bacterial metabolic homeostasis are significant consequences of treatment. Here, we describe three postulates that collectively define antibiotic efficacy in the context of bacterial metabolism: (1) antibiotics alter the metabolic state of bacteria, which contributes to the resulting death or stasis; (2) the metabolic state of bacteria influences their susceptibility to antibiotics; and (3) antibiotic efficacy can be enhanced by altering the metabolic state of bacteria. Altogether, we aim to emphasize the close relationship between bacterial metabolism and antibiotic efficacy as well as propose areas of exploration to develop novel antibiotics that optimally exploit bacterial metabolic networks.
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                Author and article information

                Contributors
                mark@msbchem.com
                Journal
                J Antibiot (Tokyo)
                J. Antibiot
                The Journal of Antibiotics
                Nature Publishing Group UK (London )
                0021-8820
                1881-1469
                10 March 2020
                2020
                : 73
                : 6
                : 329-364
                Affiliations
                ISNI 0000 0000 9320 7537, GRID grid.1003.2, Centre for Clinical Research, Faculty of Medicine, , The University of Queensland, Royal Brisbane and Women’s Hospital Complex, ; Herston, Brisbane, QLD 4072 Australia
                Author information
                http://orcid.org/0000-0001-6689-4236
                http://orcid.org/0000-0003-2079-4437
                Article
                291
                10.1038/s41429-020-0291-8
                7223789
                32152527
                0c58875e-8e5a-4ee6-84db-d4d45b639009
                © The Author(s), under exclusive licence to the Japan Antibiotics Research Association 2020

                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
                : 17 December 2019
                : 30 January 2020
                : 30 January 2020
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100000925, Department of Health | National Health and Medical Research Council (NHMRC);
                Award ID: APP1177777
                Award Recipient :
                Categories
                Review Article
                Custom metadata
                © The Author(s), under exclusive licence to the Japan Antibiotics Research Association 2020

                Infectious disease & Microbiology
                drug development,antimicrobials,medicinal chemistry
                Infectious disease & Microbiology
                drug development, antimicrobials, medicinal chemistry

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