Optimization of globomycin analogs as novel gram-negative antibiotics |
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| Institution: | 1. Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA;2. Pharmaron Beijing Co., Ltd, No. 6 Taihe Road, BDA, Beijing 100176, PR China;1. Department of Pharmacology, Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA, USA;2. Hoxworth Blood Center, University of Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA;3. Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, PA, USA;1. Departamento de Química Orgánica and UMYMFOR (CONICET–FCEyN), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellón 2, Ciudad Universitaria, C1428EHA Buenos Aires, Argentina;2. Center for Tropical and Emerging Global Diseases and Department of Cellular Biology, University of Georgia, Athens, GA 30602, USA;3. Departamento de Química Orgánica and CIHIDECAR, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellón 2, Ciudad Universitaria, C1428EHA Buenos Aires, Argentina;1. Department of Cellular and Molecular Physiology and NIHR Liverpool Pancreas Biomedical Research Unit, The University of Liverpool, Crown Street, Liverpool L69 3BX, UK;1. Normandie Univ., COBRA, UMR 6014 et FR 3038, Univ. Rouen, INSA Rouen, CNRS, 1 rue Tesnière, 76821 Mont Saint-Aignan Cedex, France;2. Immunopathologie et Chimie Thérapeutique, Institut de Biologie Moléculaire et Cellulaire CNRS-UPR3572 et FRC 1589, 15 rue Descartes, 67084 Strasbourg Cedex, France;3. Institut Charles Gerhardt UMR 5253 CNRS-UM2-UM1-ENSCM 8, rue de l’Ecole Normale, 34296 Montpellier Cedex 5, France;1. Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, VA 24061, United States;2. Department of Biochemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, VA 24061, United States;1. Department of Organic and Inorganic Chemistry, Science Centre, Federal University of Ceará, 60455-970 Fortaleza, CE, Brazil;2. Department of Pharmacy, Faculty of Pharmacy, Odontology and Nursing, Federal University of Ceará, 60430-372 Fortaleza, CE, Brazil;3. Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, 60430-270 Fortaleza, CE, Brazil |
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| Abstract: | Discovery of novel classes of Gram-negative antibiotics with activity against multi-drug resistant infections is a critical unmet need. As an essential member of the lipoprotein biosynthetic pathway, lipoprotein signal peptidase II (LspA) is an attractive target for antibacterial drug discovery, with the natural product inhibitor globomycin offering a modestly-active starting point. Informed by structure-based design, the globomycin depsipeptide was optimized to improve activity against E. coli. Backbone modifications, together with adjustment of physicochemical properties, afforded potent compounds with good in vivo pharmacokinetic profiles. Optimized compounds such as 51 (E. coli MIC 3.1 μM) and 61 (E. coli MIC 0.78 μM) demonstrate broad spectrum activity against gram-negative pathogens and may provide opportunities for future antibiotic discovery. |
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| Keywords: | Signal peptidase LspA Globomycin Gram-negative |
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