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Optimization of globomycin analogs as novel gram-negative antibiotics.

Authors
  • Garland, Keira1
  • Pantua, Homer1
  • Braun, Marie-Gabrielle1
  • Burdick, Daniel J1
  • Castanedo, Georgette M1
  • Chen, Yi-Chen1
  • Cheng, Yun-Xing2
  • Cheong, Jonathan1
  • Daniels, Blake1
  • Deshmukh, Gauri1
  • Fu, Yuhong2
  • Gibbons, Paul1
  • Gloor, Susan L1
  • Hua, Rongbao2
  • Labadie, Sharada1
  • Liu, Xiongcai2
  • Pastor, Richard1
  • Stivala, Craig1
  • Xu, Min1
  • Xu, Yiming1
  • And 3 more
  • 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. , (China)
  • 3 Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: [email protected]
Type
Published Article
Journal
Bioorganic & medicinal chemistry letters
Publication Date
Aug 05, 2020
Volume
30
Issue
20
Pages
127419–127419
Identifiers
DOI: 10.1016/j.bmcl.2020.127419
PMID: 32768648
Source
Medline
Keywords
Language
English
License
Unknown

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. Copyright © 2020 Elsevier Ltd. All rights reserved.

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