Publications by authors named "Lynn McCloskey"

11 Publications

  • Page 1 of 1

Discovery of piperazic acid peptide deformylase inhibitors with in vivo activity for respiratory tract and skin infections.

Bioorg Med Chem Lett 2019 08 16;29(16):2410-2414. Epub 2019 May 16.

GlaxoSmithKline, 1250 S. Collegeville Rd., Collegeville, PA 19426, USA.

The discovery of a novel series of peptide deformylase inhibitors incorporating a piperazic acid amino acid found in nature is described. These compounds demonstrated potent in vitro enzymatic potency and antimicrobial activity. Crystal structure analysis revealed the piperazic acid optimized a key contact with the PDF protein that accounted for the increased enzymatic potency of these compounds. We describe lead optimization of the P3' region of the series that resulted in a compound with good potency against three target organisms. One molecule showed in vivo efficacy in a rat respiratory infection model but ultimately did not meet candidate progression criteria.
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http://dx.doi.org/10.1016/j.bmcl.2019.05.028DOI Listing
August 2019

Structure-guided design of antibacterials that allosterically inhibit DNA gyrase.

Bioorg Med Chem Lett 2019 06 22;29(11):1407-1412. Epub 2019 Mar 22.

GlaxoSmithKline, Collegeville, PA 19426, USA. Electronic address:

A series of DNA gyrase inhibitors were designed based on the X-ray structure of a parent thiophene scaffold with the objective to improve biochemical and whole-cell antibacterial activity, while reducing cardiac ion channel activity. The binding mode and overall design hypothesis of one series was confirmed with a co-crystal structure with DNA gyrase. Although some analogs retained both biochemical activity and whole-cell antibacterial activity, we were unable to significantly improve the activity of the series and analogs retained activity against the cardiac ion channels, therefore we stopped optimization efforts.
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http://dx.doi.org/10.1016/j.bmcl.2019.03.029DOI Listing
June 2019

Prioritizing multiple therapeutic targets in parallel using automated DNA-encoded library screening.

Nat Commun 2017 07 17;8:16081. Epub 2017 Jul 17.

GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, Madrid 28760, Spain.

The identification and prioritization of chemically tractable therapeutic targets is a significant challenge in the discovery of new medicines. We have developed a novel method that rapidly screens multiple proteins in parallel using DNA-encoded library technology (ELT). Initial efforts were focused on the efficient discovery of antibacterial leads against 119 targets from Acinetobacter baumannii and Staphylococcus aureus. The success of this effort led to the hypothesis that the relative number of ELT binders alone could be used to assess the ligandability of large sets of proteins. This concept was further explored by screening 42 targets from Mycobacterium tuberculosis. Active chemical series for six targets from our initial effort as well as three chemotypes for DHFR from M. tuberculosis are reported. The findings demonstrate that parallel ELT selections can be used to assess ligandability and highlight opportunities for successful lead and tool discovery.
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http://dx.doi.org/10.1038/ncomms16081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5520047PMC
July 2017

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

Discovery and Characterization of a Class of Pyrazole Inhibitors of Bacterial Undecaprenyl Pyrophosphate Synthase.

J Med Chem 2016 Aug 20;59(15):7299-304. Epub 2016 Jul 20.

GlaxoSmithKline , 1250 S. Collegeville Road, Collegeville, Pennsylvania 19426, United States.

Undecaprenyl pyrophosphate synthase (UppS) is an essential enzyme in bacterial cell wall synthesis. Here we report the discovery of Staphylococcus aureus UppS inhibitors from an Encoded Library Technology screen and demonstrate binding to the hydrophobic substrate site through cocrystallography studies. The use of bacterial strains with regulated uppS expression and inhibitor resistant mutant studies confirmed that the whole cell activity was the result of UppS inhibition, validating UppS as a druggable antibacterial target.
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http://dx.doi.org/10.1021/acs.jmedchem.6b00746DOI Listing
August 2016

Frequency of Spontaneous Resistance to Peptide Deformylase Inhibitor GSK1322322 in Haemophilus influenzae, Staphylococcus aureus, Streptococcus pyogenes, and Streptococcus pneumoniae.

Antimicrob Agents Chemother 2015 Aug 26;59(8):4644-52. Epub 2015 May 26.

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

The continuous emergence of multidrug-resistant pathogenic bacteria is compromising the successful treatment of serious microbial infections. GSK1322322, a novel peptide deformylase (PDF) inhibitor, shows good in vitro antibacterial activity and has demonstrated safety and efficacy in human proof-of-concept clinical studies. In vitro studies were performed to determine the frequency of resistance (FoR) to this antimicrobial agent in major pathogens that cause respiratory tract and skin infections. Resistance to GSK1322322 occurred at high frequency through loss-of-function mutations in the formyl-methionyl transferase (FMT) protein in Staphylococcus aureus (4/4 strains) and Streptococcus pyogenes (4/4 strains) and via missense mutations in Streptococcus pneumoniae (6/21 strains), but the mutations were associated with severe in vitro and/or in vivo fitness costs. The overall FoR to GSK1322322 was very low in Haemophilus influenzae, with only one PDF mutant being identified in one of four strains. No target-based mutants were identified from S. pyogenes, and only one or no PDF mutants were isolated in three of the four S. aureus strains studied. In S. pneumoniae, PDF mutants were isolated from only six of 21 strains tested; an additional 10 strains did not yield colonies on GSK1322322-containing plates. Most of the PDF mutants characterized from those three organisms (35/37 mutants) carried mutations in residues at or in close proximity to one of three highly conserved motifs that are part of the active site of the PDF protein, with 30 of the 35 mutations occurring at position V71 (using the S. pneumoniae numbering system).
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http://dx.doi.org/10.1128/AAC.00484-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4505285PMC
August 2015

Fragment-based discovery of 6-azaindazoles as inhibitors of bacterial DNA ligase.

ACS Med Chem Lett 2013 Dec 18;4(12):1208-12. Epub 2013 Oct 18.

Astex Pharmaceuticals Inc., 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom.

Herein we describe the application of fragment-based drug design to bacterial DNA ligase. X-ray crystallography was used to guide structure-based optimization of a fragment-screening hit to give novel, nanomolar, AMP-competitive inhibitors. The lead compound 13 showed antibacterial activity across a range of pathogens. Data to demonstrate mode of action was provided using a strain of S. aureus, engineered to overexpress DNA ligase.
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http://dx.doi.org/10.1021/ml4003277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4027552PMC
December 2013

Genetic characterization of Vga ABC proteins conferring reduced susceptibility to pleuromutilins in Staphylococcus aureus.

Antimicrob Agents Chemother 2008 Dec 6;52(12):4507-9. Epub 2008 Oct 6.

Department of Microbiology, ID-CEDD, GlaxoSmithKline, Collegeville, Pennsylvania 19426, USA.

Retapamulin MICs of > or =2 microg/ml were noted for 6 of 5,676 S. aureus recent clinical isolates evaluated. The ABC proteins VgaAv and VgaA were found to be responsible for the reduced susceptibility to pleuromutilins exhibited by these six isolates.
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http://dx.doi.org/10.1128/AAC.00915-08DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2592886PMC
December 2008

Stepwise exposure of Staphylococcus aureus to pleuromutilins is associated with stepwise acquisition of mutations in rplC and minimally affects susceptibility to retapamulin.

Antimicrob Agents Chemother 2007 Jun 2;51(6):2048-52. Epub 2007 Apr 2.

UP1345, GlaxoSmithKline, 1250 S. Collegeville Road, Collegeville, PA 19426, USA.

To assess their effects on susceptibility to retapamulin in Staphylococcus aureus, first-, second-, and third-step mutants with elevated MICs to tiamulin and other investigational pleuromutilin compounds were isolated and characterized through exposure to high drug concentrations. All first- and second-step mutations were in rplC, encoding ribosomal protein L3. Most third-step mutants acquired a third mutation in rplC. While first- and second-step mutations did cause an elevation in tiamulin and retapamulin MICs, a significant decrease in activity was not seen until a third mutation was acquired. All third-step mutants exhibited severe growth defects, and faster-growing variants arose at a high frequency from most isolates. These faster-growing variants were found to be more susceptible to pleuromutilins. In the case of a mutant with three alterations in rplC, the fast-growing variants acquired an additional mutation in rplC. In the case of fast-growing variants of isolates with two mutations in rplC and at least one mutation at an unmapped locus, one of the two rplC mutations reverted to wild type. These data indicate that mutations in rplC that lead to pleuromutilin resistance have a direct, negative effect on fitness. While reduction in activity of retapamulin against S. aureus can be seen through mutations in rplC, it is likely that target-specific resistance to retapamulin will be slow to emerge due to the need for three mutations for a significant effect on activity and the fitness cost of each mutational step.
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http://dx.doi.org/10.1128/AAC.01066-06DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1891380PMC
June 2007

Selection of retapamulin, a novel pleuromutilin for topical use.

Antimicrob Agents Chemother 2006 Nov;50(11):3882-5

Department of Microbiology Research, MMPD CEDD, GlaxoSmithKline Pharmaceuticals, 1250 S. Collegeville Rd, Collegeville, PA 19426-0989, USA.

The in vitro activity of retapamulin was determined and compared to that of topical and community antibiotics. The MIC(90)s of retapamulin against Staphylococcus aureus and Streptococcus pyogenes were 0.12 microg/ml and 0.016 microg/ml, respectively. Retapamulin has a low propensity to select resistance and produces an in vitro postantibiotic effect.
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http://dx.doi.org/10.1128/AAC.00178-06DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1635201PMC
November 2006