title: A class of selective antibacterials derived from a protein kinase inhibitor pharmacophore.
abstract: 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.
authors.affiliation: Pfizer, Inc., Ann Arbor, MI 48105, USA. richard.miller2@pfizer.com
authors.forename: J Richard
authors.initials: JR
authors.lastname: Miller
authors.forename: Steve
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authors.forename: Igor
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authors.lastname: Mochalkin
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authors.lastname: Bowman
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authors.initials: HJ
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authors.forename: Michael D
authors.initials: MD
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authors.forename: Alla
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authors.lastname: Karnovsky
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authors.lastname: Kuhn
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authors.lastname: Limberakis
authors.forename: Jia Y
authors.initials: JY
authors.lastname: Liu
authors.forename: Shawn
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authors.forename: W Thomas
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authors.lastname: Mueller
authors.forename: Lakshmi
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authors.lastname: Narasimhan
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authors.lastname: Ogden
authors.forename: Jeff
authors.initials: J
authors.lastname: Ohren
authors.forename: J V N Vara
authors.initials: JV
authors.lastname: Prasad
authors.forename: John A
authors.initials: JA
authors.lastname: Shelly
authors.forename: Laura
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authors.lastname: Skerlos
authors.forename: Mark
authors.initials: M
authors.lastname: Sulavik
authors.forename: V Hayden
authors.initials: VH
authors.lastname: Thomas
authors.forename: Steve
authors.initials: S
authors.lastname: VanderRoest
authors.forename: LiAnn
authors.initials: L
authors.lastname: Wang
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Wang
authors.forename: Amy
authors.initials: A
authors.lastname: Whitton
authors.forename: Tong
authors.initials: T
authors.lastname: Zhu
authors.forename: C Kendall
authors.initials: CK
authors.lastname: Stover
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D019731:Carbon-Nitrogen Ligases / Q000037:antagonists & inhibitors*; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D006090:Gram-Negative Bacteria / Q000187:drug effects / Q000201:enzymology; D006193:Haemophilus influenzae / Q000187:drug effects / Q000201:enzymology; D001936:Moraxella catarrhalis / Q000187:drug effects / Q000201:enzymology; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D054852:Small Molecule Libraries
chemical_list: D000900:Anti-Bacterial Agents; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D054852:Small Molecule Libraries; D019731:Carbon-Nitrogen Ligases; C019791:biotin carboxylase