Publications by authors named "Dongzhao Chen"

7 Publications

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Thiophene antibacterials that allosterically stabilize DNA-cleavage complexes with DNA gyrase.

Proc Natl Acad Sci U S A 2017 05 15;114(22):E4492-E4500. Epub 2017 May 15.

Antibacterial Discovery Performance Unit, Infectious Diseases Therapy Area Unit, GlaxoSmithKline, Collegeville, PA 19426;

A paucity of novel acting antibacterials is in development to treat the rising threat of antimicrobial resistance, particularly in Gram-negative hospital pathogens, which has led to renewed efforts in antibiotic drug discovery. Fluoroquinolones are broad-spectrum antibacterials that target DNA gyrase by stabilizing DNA-cleavage complexes, but their clinical utility has been compromised by resistance. We have identified a class of antibacterial thiophenes that target DNA gyrase with a unique mechanism of action and have activity against a range of bacterial pathogens, including strains resistant to fluoroquinolones. Although fluoroquinolones stabilize double-stranded DNA breaks, the antibacterial thiophenes stabilize gyrase-mediated DNA-cleavage complexes in either one DNA strand or both DNA strands. X-ray crystallography of DNA gyrase-DNA complexes shows the compounds binding to a protein pocket between the winged helix domain and topoisomerase-primase domain, remote from the DNA. Mutations of conserved residues around this pocket affect activity of the thiophene inhibitors, consistent with allosteric inhibition of DNA gyrase. This druggable pocket provides potentially complementary opportunities for targeting bacterial topoisomerases for antibiotic development.
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http://dx.doi.org/10.1073/pnas.1700721114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5465892PMC
May 2017

Novel tricyclics (e.g., GSK945237) as potent inhibitors of bacterial type IIA topoisomerases.

Bioorg Med Chem Lett 2016 05 31;26(10):2464-2469. Epub 2016 Mar 31.

Infectious Diseases CEDD, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA.

During the course of our research on the lead optimisation of the NBTI (Novel Bacterial Type II Topoisomerase Inhibitors) class of antibacterials, we discovered a series of tricyclic compounds that showed good Gram-positive and Gram-negative potency. Herein we will discuss the various subunits that were investigated in this series and report advanced studies on compound 1 (GSK945237) which demonstrates good PK and in vivo efficacy properties.
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http://dx.doi.org/10.1016/j.bmcl.2016.03.106DOI Listing
May 2016

Potent sub-MIC effect of GSK1322322 and other peptide deformylase inhibitors on in vitro growth of Staphylococcus aureus.

Antimicrob Agents Chemother 2014 28;58(1):290-6. Epub 2013 Oct 28.

Antibacterial Discovery Performance Unit, Infectious Disease Therapeutic Area, GlaxoSmithKline, Collegeville, Pennsylvania, USA.

Peptide deformylase (PDF), a clinically unexploited antibacterial target, plays an essential role in protein maturation. PDF inhibitors, therefore, represent a new antibiotic class with a unique mode of action that provides an alternative therapy for the treatment of infections caused by drug-resistant pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). GSK1322322 is a novel PDF inhibitor that is in phase II clinical development for the treatment of lower respiratory tract and skin infections. We have discovered that PDF inhibitors can prevent S. aureus in vitro growth for up to 6 h at concentrations 8- to 32-fold below their MICs. This phenomenon seems specific to PDF inhibitors, as none of the antimicrobial agents with alternative mechanisms of action tested show such a potent and widespread effect. It also appears limited to S. aureus, as PDF inhibitors do not show such an inhibition of growth at sub-MIC levels in Streptococcus pneumoniae or Haemophilus influenzae. Analysis of the effect of GSK1322322 on the early growth of 100 randomly selected S. aureus strains showed that concentrations equal to or below 1/8× MIC inhibited growth of 91% of the strains tested for 6 h, while the corresponding amount of moxifloxacin or linezolid only affected the growth of 1% and 6% of strains, respectively. Furthermore, the sub-MIC effect demonstrated by GSK1322322 appears more substantial on those strains at the higher end of the MIC spectrum. These effects may impact the clinical efficacy of GSK1322322 in serious infections caused by multidrug-resistant S. aureus.
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http://dx.doi.org/10.1128/AAC.01292-13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3910740PMC
September 2014

Novel hydroxyl tricyclics (e.g., GSK966587) as potent inhibitors of bacterial type IIA topoisomerases.

Bioorg Med Chem Lett 2013 Oct 17;23(19):5437-41. Epub 2013 Jul 17.

Diseases of the Developing World CEDD, GlaxoSmithKline, Madrid, Spain.

During the course of our research to find novel mode of action antibacterials, we discovered a series of hydroxyl tricyclic compounds that showed good potency against Gram-positive and Gram-negative pathogens. These compounds inhibit bacterial type IIA topoisomerases. Herein we will discuss structure-activity relationships in this series and report advanced studies on compound 1 (GSK966587) which demonstrates good PK and in vivo efficacy properties. X-ray crystallographic studies were used to provide insight into the structural basis for the difference in antibacterial potency between enantiomers.
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http://dx.doi.org/10.1016/j.bmcl.2013.07.013DOI Listing
October 2013

Novel amino-piperidines as potent antibacterials targeting bacterial type IIA topoisomerases.

Bioorg Med Chem Lett 2011 Dec 10;21(24):7489-95. Epub 2011 Oct 10.

Diseases of the Developing World CEDD, GlaxoSmithKline, Calle Severo Ochoa 2, 28760, Tres Cantos, Madrid, Spain.

We have identified a series of amino-piperidine antibacterials with a good broad spectrum potency. We report the investigation of various subunits in this series and advanced studies on compound 8. Compound 8 possesses good pharmacokinetics, broad spectrum antibacterial activity and demonstrates oral efficacy in a rat lung infection model.
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http://dx.doi.org/10.1016/j.bmcl.2011.09.117DOI Listing
December 2011

Novel cyclohexyl-amides as potent antibacterials targeting bacterial type IIA topoisomerases.

Bioorg Med Chem Lett 2011 Dec 10;21(24):7483-8. Epub 2011 Oct 10.

Diseases of the Developing World CEDD, GlaxoSmithKline, Calle Severo Ochoa, 2, 28760, Tres Cantos, Madrid, Spain.

As part of our wider efforts to exploit novel mode of action antibacterials, we have discovered a series of cyclohexyl-amide compounds that has good Gram positive and Gram negative potency. The mechanism of action is via inhibition of bacterial topoisomerases II and IV. We have investigated various subunits in this series and report advanced studies on compound 7 which demonstrates good PK and in vivo efficacy properties.
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http://dx.doi.org/10.1016/j.bmcl.2011.09.114DOI Listing
December 2011

A rapid microtiter plate assay for measuring the effect of compounds on Staphylococcus aureus membrane potential.

J Microbiol Methods 2010 Nov 27;83(2):254-6. Epub 2010 Aug 27.

Antibacterial Discovery Performance Unit, Infectious Diseases Center of Excellence in Drug Discovery, GlaxoSmithKline Pharmaceuticals, Collegeville, PA 19426, United States.

We developed a homogenous microtiter based assay using the cationic dye 3, 3'-Diethyloxacarbocyanine iodide, DiOC2(3), to measure the effect of compounds on membrane potential in Staphylococcus aureus. In a screen of 372 compounds from a synthetic compound collection with anti-Escherichia coli activity due to unknown modes of action at least 17% demonstrated potent membrane activity, enabling rapid discrimination of nuisance compounds.
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http://dx.doi.org/10.1016/j.mimet.2010.08.012DOI Listing
November 2010