Peptide deformylase (PDF) has emerged as an important antibacterial drug target. Considerable effort is being directed toward developing peptidic and non-peptidic inhibitors for this metalloprotein. In this work, the known peptidic inhibitor BB-3497 and its various ionization and tautomeric states are evaluated for their inhibition efficiency against PDF using a molecular mechanics (MM) approach as well as a mixed quantum mechanics/molecular mechanics (QM/MM) approach, with an aim to understand the interactions in the binding site. The evaluated Gibbs energies of binding with the mixed QM/MM approach are shown to have the best predictive power. The experimental pose is found to have the most negative Gibbs energy of binding, and also the smallest strain energy. A quantum mechanical evaluation of the active site reveals the requirement of strong chelation by the ligand with the metal ion. The investigated ligand chelates the metal ion through the two oxygens of its reverse hydroxamate moiety, particularly the N-O(-) oxygen, forming strong covalent bonds with the metal ion, which is penta-coordinated. In the uninhibited state, the metal ion is tetrahedrally coordinated, and hence chelation with the inhibitor is associated with an increase of the metal ion coordination. Thus, the strong binding of the ligand at the binding site is accounted for.

01 Sep 2009·International Journal of Antimicrobial AgentsQ2 · MEDICINE

In vitro and ex vivo activity of peptide deformylase inhibitors against Mycobacterium tuberculosis H37Rv

Q2 · MEDICINE

Article

Author: G.K. Khuller ; A.J. Kanwar ; Sadhna Sharma ; Anshika Sharma

Bacterial peptide deformylase (PDF) catalyses removal of the N-terminal formyl group of proteins and is essential for protein maturation, growth and survival of bacteria. Thus, PDF appears to be a good antimycobacterial drug target. In the present study, various well-known PDF inhibitors, such as BB-3497, actinonin, 1,10-phenanthroline, hydroxylamine hydrochloride and galardin, were selected to evaluate their inhibitory activity against Mycobacterium tuberculosis. All compounds were found to be active against M. tuberculosis, with MIC(90) values (lowest drug concentration at which 90% of growth was inhibited on the basis of CFU enumeration) ranging from 0.2 mg/L to 74 mg/L. BB-3497 and 1,10-phenanthroline exhibited potent in vitro antimycobacterial activity, and also showed synergism with isoniazid and rifampicin. All compounds showed a bacteriostatic mode of inhibition. Under ex vivo conditions and short-course chemotherapy, BB-3497 and actinonin were found to be significantly active, with BB-3497 exhibiting comparable efficacy to that of isoniazid. Collectively, promising activities of PDF inhibitors such as BB-3497 and actinonin suggest their potential use against M. tuberculosis.

15 Jul 2006·Journal of BacteriologyQ3 · BIOLOGY

Phylogenomic and Biochemical Characterization of ThreeLegionella pneumophilaPolypeptide Deformylases

Q3 · BIOLOGY

Article

Author: Brown, James R. ; Taylor, Amy N. ; Kerrigan, John J. ; Holmes, David ; Aubart, Kelly M. ; Van Aller, Glenn S. ; Lai, Zhihong ; Zalacain, Magdalena ; Huang, Jianzhong ; Liu, Wu-Schyong ; Trulli, Janice M.

ABSTRACTLegionella pneumophilais a gram-negative facultative intracellular human pathogen that can cause fatal Legionnaires' disease. Polypeptide deformylase (PDF) is a novel broad-spectrum antibacterial target, and reports of inhibitors of PDF with potent activities againstL. pneumophilahave been published previously. Here, we report the identification of not one but three putativepdfgenes,pdfA,pdfB, andpdfC, in the complete genome sequences of three strains ofL. pneumophila. Phylogenetic analysis showed thatL. pneumophilaPdfA is most closely related to the commonly known γ-proteobacterial PDFs encoded by the genedef.PdfB and PdfC are more divergent and do not cluster with any specific bacterial or eukaryotic PDF. All three putativepdfgenes fromL. pneumophilastrain Philadelphia 1 have been cloned, and their encoded products have been overexpressed inEscherichia coliand purified. Enzymatic characterization shows that the purified PDFs with Ni2+substituted are catalytically active and able to remove the N-formyl group from several synthetic polypeptides, although they appear to have different substrate specificities. Surprisingly, while PdfA and PdfB with Zn2+substituted are much less active than the Ni2+forms of each enzyme, PdfC with Zn2+substituted was as active as the Ni2+form for the fMA substrate and exhibited substrate specificity different from that of Ni2+PdfC. Furthermore, the catalytic activities of these enzymes are potently inhibited by a known small-molecule PDF inhibitor, BB-3497, which also inhibits the extracellular growth ofL. pneumophila. These results indicate that even thoughL. pneumophilahas three PDFs, they can be effectively inhibited by PDF inhibitors which can, therefore, have potent anti-L. pneumophilaactivity.

100 Deals associated with BB-3497

R&D Status

10 top R&D records.

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Bacterial Infections	NDA/BLA	GB	Ligand UK Ltd.	-
Respiratory Tract Infections	Preclinical	GB	Birmingham City Hospital	03 Jan 2002

Clinical Result

Indication

Phase

Evaluation

View All Results

Translational Medicine

Boost your research with our translational medicine data.

view full example data

Deal

Boost your decision using our deal data.

view full example data

Core Patent

Boost your research with our Core Patent data.

view full example data

Clinical Trial

Identify the latest clinical trials across global registries.

view full example data

Approval

Accelerate your research with the latest regulatory approval information.

view full example data

Regulation

Understand key drug designations in just a few clicks with Synapse.

view full example data

Chat with Hiro

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis


No Data

BB-3497

Overview

Basic Info

Related

R&D Status

Clinical Result

Translational Medicine

Deal

Core Patent

Clinical Trial

Approval

Regulation