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

Pfizer, Inc., Ann Arbor, MI 48105, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 02/2009; 106(6):1737-42. DOI: 10.1073/pnas.0811275106
Source: PubMed


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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Available from: Igor Mochalkin,
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    • "Xie et al. [2] [3] [4] proposed an efficient and robust algorithm called SMAP, which quantitatively characterizes the geometric properties of proteins. Ligand binding sites predicted by SMAP have been experimentally validated [4] [5] [6] [7]. SMAP has also been applied to drug design problems, such as constructing drug-target interaction networks [4], designing polypharmacology drugs [5], assigning old drugs to new indications [6], and predicting the side effects of drugs [8, 9]. "
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    ABSTRACT: The proteome-wide analysis of protein-ligand binding sites and their interactions with ligands is important in structure-based drug design and in understanding ligand cross reactivity and toxicity. The well-known and commonly used software, SMAP, has been designed for 3D ligand binding site comparison and similarity searching of a structural proteome. SMAP can also predict drug side effects and reassign existing drugs to new indications. However, the computing scale of SMAP is limited. We have developed a high availability, high performance system that expands the comparison scale of SMAP. This cloud computing service, called Cloud-PLBS, combines the SMAP and Hadoop frameworks and is deployed on a virtual cloud computing platform. To handle the vast amount of experimental data on protein-ligand binding site pairs, Cloud-PLBS exploits the MapReduce paradigm as a management and parallelizing tool. Cloud-PLBS provides a web portal and scalability through which biologists can address a wide range of computer-intensive questions in biology and drug discovery.
    05/2013; 2013(1):170356. DOI:10.1155/2013/170356
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    • "The dramatic increase in the number of pathogenic bacteria with extensive resistance to antibiotics has been well documented (Nathan, 2012; Spí zek et al., 2010). Thus, there is a pressing need for new targets and biotin carboxylase has been validated as a novel target for antibacterial development (Miller et al., 2009; Mochalkin et al., 2009). Given that the protein-protein interface in E. coli BCCP-BC appears to be unique and presumably required for enzymatic activity, this greatly expands the number of potential target sites beyond just the traditional active sites. "
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    ABSTRACT: Acetyl-coenzyme A (acetyl-CoA) carboxylase is a biotin-dependent, multifunctional enzyme that catalyzes the regulated step in fatty acid synthesis. The Escherichia coli enzyme is composed of a homodimeric biotin carboxylase (BC), biotinylated biotin carboxyl carrier protein (BCCP), and an α2β2 heterotetrameric carboxyltransferase. This enzyme complex catalyzes two half-reactions to form malonyl-coenzyme A. BC and BCCP participate in the first half-reaction, whereas carboxyltransferase and BCCP are involved in the second. Three-dimensional structures have been reported for the individual subunits; however, the structural basis for how BCCP reacts with the carboxylase or transferase is unknown. Therefore, we report here the crystal structure of E. coli BCCP complexed with BC to a resolution of 2.49 Å. The protein-protein complex shows a unique quaternary structure and two distinct interfaces for each BCCP monomer. These BCCP binding sites are unique compared to phylogenetically related biotin-dependent carboxylases and therefore provide novel targets for developing antibiotics against bacterial acetyl-CoA carboxylase.
    Structure 03/2013; 21(4). DOI:10.1016/j.str.2013.02.001 · 5.62 Impact Factor
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    • "In the genomic revolution thousands of targets were identified against bacterial pathogens (Miller et al., 2009). Inhibition of fatty acid biosynthesis could be one of the best ways to control the microbial agents. "
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    ABSTRACT: Biotin carboxylase (AccC) protein plays an essential role in cell wall biosynthesis in majority of bacterial genera. Inhibition of cell wall biosynthesis might be an ideal way to control the bacterial multiplication in the host system. AccC is one of the promising targets for the antibacterial drugs production. The benzimidazole derivatives are hopeful biotin carboxylase inhibitors, which sensitizes to the Escherichia coli (E. coli) and many other bacterial species too. In steam of developing better benzimidazole derivatives, we describe a quantitative pharmacophore model of benzimidazole derivatives using Phase module of Schrödinger LLC. This model suggested that the following features are essential for ligand binding, i.e., two aromatic rings, two hydrogen bond donors, one hydrogen bond acceptor, and one hydrophobic group. Further, atom-based 3D-QSAR model was constructed using training set of 37 inhibitors. The constructed QSAR model has cross validated co-efficient value of (Q 2) 0.736 and regression co-efficient value of (R 2) 0.937. The external validation indicated that our QSAR model possessed high predicted powers with r2o value of 0.933, r2m value of 0.876. The best active and least active compounds were docked into the active site of receptor using Glide and hotspots of the active site were analyzed. The QSAR elucidated here for benzimidazole derivatives combined with their binding information will provide an opportunity to explore the chemical space to promote the potency of AccC inhibitors.
    Medicinal Chemistry Research 09/2012; 21(9):2169-2180. DOI:10.1007/s00044-011-9738-6 · 1.40 Impact Factor
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