A class of selective antibacterials derived from a protein kinase inhibitor pharmacophore.

نویسندگان

  • J Richard Miller
  • Steve Dunham
  • Igor Mochalkin
  • Craig Banotai
  • Matthew Bowman
  • Susan Buist
  • Bill Dunkle
  • Debra Hanna
  • H James Harwood
  • Michael D Huband
  • Alla Karnovsky
  • Michael Kuhn
  • Chris Limberakis
  • Jia Y Liu
  • Shawn Mehrens
  • W Thomas Mueller
  • Lakshmi Narasimhan
  • Adam Ogden
  • Jeff Ohren
  • J V N Vara Prasad
  • John A Shelly
  • Laura Skerlos
  • Mark Sulavik
  • V Hayden Thomas
  • Steve VanderRoest
  • LiAnn Wang
  • Zhigang Wang
  • Amy Whitton
  • Tong Zhu
  • C Kendall Stover
چکیده

As the need for novel antibiotic classes to combat bacterial drug resistance increases, the paucity of leads resulting from target-based antibacterial screening of pharmaceutical compound libraries is of major concern. One explanation for this lack of success is that antibacterial screening efforts have not leveraged the eukaryotic bias resulting from more extensive chemistry efforts targeting eukaryotic gene families such as G protein-coupled receptors and protein kinases. Consistent with a focus on antibacterial target space resembling these eukaryotic targets, we used whole-cell screening to identify a series of antibacterial pyridopyrimidines derived from a protein kinase inhibitor pharmacophore. In bacteria, the pyridopyrimidines target the ATP-binding site of biotin carboxylase (BC), which catalyzes the first enzymatic step of fatty acid biosynthesis. These inhibitors are effective in vitro and in vivo against fastidious gram-negative pathogens including Haemophilus influenzae. Although the BC active site has architectural similarity to those of eukaryotic protein kinases, inhibitor binding to the BC ATP-binding site is distinct from the protein kinase-binding mode, such that the inhibitors are selective for bacterial BC. In summary, we have discovered a promising class of potent antibacterials with a previously undescribed mechanism of action. In consideration of the eukaryotic bias of pharmaceutical libraries, our findings also suggest that pursuit of a novel inhibitor leads for antibacterial targets with active-site structural similarity to known human targets will likely be more fruitful than the traditional focus on unique bacterial target space, particularly when structure-based and computational methodologies are applied to ensure bacterial selectivity.

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عنوان ژورنال:
  • Proceedings of the National Academy of Sciences of the United States of America

دوره 106 6  شماره 

صفحات  -

تاریخ انتشار 2009