Baines S.D.,University of Hertfordshire |
Crowther G.S.,University of Leeds |
Freeman J.,Leeds Teaching Hospitals NHS Trust |
Todhunter S.,University of Leeds |
And 3 more authors.
Journal of Antimicrobial Chemotherapy | Year: 2015
Objectives: We investigated the efficacy of the novel antimicrobial agent SMT19969 in treating simulated Clostridium difficile infection using an in vitro human gut model. Methods: Concentrations of the predominant cultivable members of the indigenous gut microfloras and C. difficile (total and spore counts) were determined by viable counting. Cytotoxin titres were determined using cell cytotoxicity and expressed as log10 relative units (RU). Clindamycin was used to induce simulated C. difficile PCR ribotype 027 infection. Once high-level cytotoxin titres (≥4 RU) were observed, SMT19969 was instilled for 7 days. Two SMT19969 dosing regimens (31.25 and 62.5 mg/L four times daily) were evaluated simultaneously in separate experiments. MICs of SMT19969 were determined against 30 genotypically distinct C. difficile ribotypes. Results: SMT19969 was 7- and 17-fold more active against C. difficile than metronidazole and vancomycin, respectively, against a panel of genotypically distinct isolates (P<0.05). Both SMT19969 dosing regimens demonstrated little antimicrobial activity against indigenous gut microflora groups except clostridia. SMT19969 inhibited C. difficile growth and repressed C. difficile cytotoxin titres in the gut model. Conclusions: These data suggest that SMT19969 is a narrow-spectrum and potent antimicrobial agent against C. difficile. Additional studies evaluating SMT19969 in other models of C. difficile infection are warranted, with human studies to place these gut model observations in context. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.
Sloane D.A.,Yorkshire Cancer Research |
Trikic M.Z.,Yorkshire Cancer Research |
Chu M.L.H.,Stanford University |
Lamers M.B.A.C.,Chesterford Research Park |
And 5 more authors.
ACS Chemical Biology | Year: 2010
The Aurora kinases regulate multiple aspects of mitotic progression, and their overexpression in diverse tumor types makes them appealing oncology targets. An intensive research effort over the past decade has led to the discovery of chemically distinct families of small molecule Aurora kinase inhibitors, many of which have demonstrated therapeutic potential in model systems. These agents are also important tools to help dissect signaling pathways that are orchestrated by Aurora kinases, and the antiproliferative target of pan-Aurora inhibitors such as VX-680 has been validated using chemical genetic techniques. In many cases the nonspecific nature of Aurora inhibitors toward unrelated kinases is well established, potentially broadening the spectrum of cancers to which these compounds might be applied. However, unambiguously demonstrating the molecular target(s) for clinical kinase inhibitors is an important challenge, one that is absolutely critical for deciphering the molecular basis of compound specificity, resistance, and efficacy. In this paper, we have investigated amino acid requirements for Aurora A sensitivity to the benzazepine-based Aurora inhibitor MLN8054 and the close analogue MLN8237, a second-generation compound that is in phase II clinical trials. A crystallographic analysis facilitated the design and biochemical investigation of a panel of resistant Aurora A mutants, a subset of which were then selected as candidate drug-resistance targets for further evaluation. Using inducible human cell lines, we show that cells expressing near-physiological levels of a functional but partially drug-resistant Aurora A T217D mutant survive in the presence of MLN8054 or MLN8237, authenticating Aurora A as a critical antiproliferative target of these compounds. © 2010 American Chemical Society.
Glawar A.F.G.,University of Oxford |
Best D.,University of Oxford |
Ayers B.J.,University of Oxford |
Miyauchi S.,University of Toyama |
And 9 more authors.
Chemistry - A European Journal | Year: 2012
The efficient scalable syntheses of 2-acetamido-1,2-dideoxy-D-galacto- nojirimycin (DGJNAc) and 2-acetamido-1,2-dideoxy-D-gluco-nojirimycin (DNJNAc) from D-glucuronolactone, as well as of their enantiomers from L-glucuronolactone, are reported. The evaluation of both enantiomers of DNJNAc and DGJNAc, along with their N-alkyl derivatives, as glycosidase inhibitors showed that DGJNAc and its N-alkyl derivatives were all inhibitors of α-GalNAcase but that none of the epimeric DNJNAc derivatives inhibited this enzyme. In contrast, both DGJNAc and DNJNAc, as well as their alkyl derivatives, were potent inhibitors of β-GlcNAcases and β-GalNAcases. Neither of the L-enantiomers showed any significant inhibition of any of the enzymes tested. Correlation of the in vitro inhibition with the cellular data, by using a free oligosaccharide analysis of the lysosomal enzyme inhibition, revealed the following structure-property relationship: hydrophobic side-chains preferentially promoted the intracellular access of iminosugars to those inhibitors with more-hydrophilic side-chain characteristics. Getting the NAc of it: Scalable syntheses of DGJNAc and DNJNAc from D-glucuronolactone are reported. DGJNAc and its N-alkyl derivatives were inhibitors of α-GalNAcase and both DGJNAc and DNJNAc were potent inhibitors of β-GlcNAcases and β-GalNAcases. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
A randomised phase 1 study to investigate safety, pharmacokinetics and impact on gut microbiota following single and multiple oral doses in healthy male subjects of SMT19969, a novel agent for Clostridium difficile infections
Vickers R.,Summit PLC |
Robinson N.,Summit PLC |
Best E.,University of Leeds |
Echols R.,753 Westport Road |
And 2 more authors.
BMC Infectious Diseases | Year: 2015
Background: Clostridium difficile infection (CDI) is a leading cause of diarrhoea in health care settings with symptoms ranging from mild and self-limiting to life threatening. SMT19969 is a novel, non-absorbable antibiotic currently under development for the treatment of CDI. Here we report the results from a Phase I study. Methods: A double-blind, randomized, placebo-controlled study assessing safety and tolerability of single and multiple oral doses of SMT19969 in healthy volunteers. Pharmacokinetic assessments included blood and faecal sampling. The effect of food on systemic exposure and analysis of the gut microbiota were also included. Results: Fifty-six healthy male subjects were enrolled. Following single oral doses of up to 2,000 mg in the fasted state, plasma concentrations of SMT19969 were generally below the lower limit of quantification. In the fed state levels ranged from 0.102 to 0.296 ng/mL after single dosing and after repeat dosing at Day 10 from 0.105 to 0.305 ng/mL. Following single and multiple oral doses of SMT19969, mean daily faecal concentrations increased with increasing dose level and were significantly above the typical MIC range for C. difficile (0.06-0.5_μg/mL). At 200 mg BID, mean (± SD) faecal concentrations of 1,466 (±547) _μg/g and 1,364 (±446) _μg/g were determined on days 5 and 10 of dosing respectively. No notable metabolites were detected in faeces. Overall, all doses of SMT19969 were well tolerated both as single oral doses or BID oral doses for 10 days. The majority (88%) of adverse events (AEs) were classified as gastrointestinal disorders and were mild in severity, resolving without treatment. The gut microbiota was analysed in the multiple dose groups with minimal changes observed in the bacterial groups analysed except for total clostridia which were reduced to below the limit of detection by day 4 of dosing. Conclusions: Oral administration of SMT19969 was considered safe and well tolerated and was associated with negligible plasma concentrations after single and multiple doses. In addition, minimal disruption of normal gut microbiota was noted, confirming the highly selective spectrum of the compound. These results support the further clinical development of SMT19969 as an oral therapy for CDI. © 2015 Vickers et al.; licensee BioMed Central.
Sattar A.,Evotec |
Thommes P.,Evotec |
Payne L.,Evotec |
Warn P.,Evotec |
Vickers R.J.,Summit plc
Journal of Antimicrobial Chemotherapy | Year: 2014
Objectives: SMT19969 is a novel narrow-spectrum antimicrobial under development for the treatment of Clostridium difficile infection (CDI). The objectives were to assess the relative efficacies of SMT19969, vancomycin and fidaxomicin in the hamster model of CDI. Methods: Hamsters were infected with either C. difficile BI1 (ribotype 027) or C. difficile 630 (ribotype 012) prior to treatment with vehicle, SMT19969, fidaxomicin or vancomycin for 5 days. Animals were further monitored through to day 28 and survival recorded. Plasma and gastrointestinal concentrations of SMT19969 following single and repeat administration in infected hamsters were determined. Results: Following infection with C. difficile BI1, treatmentwith SMT19969, vancomycin and fidaxomicin resulted in 100% survival during the 5 day dosing period, with 90%-100% of animals receiving SMT19969 and fidaxomicin surviving during the post-dosing follow-up period. Whilst protective during treatment, onset of mortality was observed on day 11 in animals treated with vancomycin, with a 10% survival recorded by day 28. Similar results were observed for SMT19969 and vancomycin following infection with C. difficile 630, with day 28 survival rates of 80%-100%and 0%, respectively. Fidaxomicin protected animals infectedwith C. difficile 630 frommortality during dosing, although day 28 survival rates varied from0%to 40%depending on dose. Plasmalevels of SMT19969were typically below the limit of quantification, but levels in the gastrointestinal tract remained far in excess of the MIC. Conclusions: These data show that SMT19969 is highly effective at treating both acute infection and preventing recurrent disease and support continued investigation of SMT19969 as a potential therapy for CDI. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.
Zhang W.,CAS Beijing National Laboratory for Molecular |
Sato K.,University of Toyama |
Kato A.,University of Toyama |
Jia Y.-M.,CAS Beijing National Laboratory for Molecular |
And 7 more authors.
Organic Letters | Year: 2011
Total synthesis of the proposed structure of (-)-hyacinthacine C 5 and its epimers at C6 and C7 is described. A key step of the synthesis was the construction of the bicyclic pyrrolizidine system by means of a nucleophilic addition of a dithiane to a cyclic nitrone followed by a Cope-House cyclization. © 2011 American Chemical Society.
Hu X.-G.,CAS Beijing National Laboratory for Molecular |
Hu X.-G.,University of Chinese Academy of Sciences |
Bartholomew B.,Phytoquest Ltd |
Nash R.J.,Phytoquest Ltd |
And 7 more authors.
Organic Letters | Year: 2010
(+)-Steviamine, the enantiomer of the natural (-)-steviamine, and its corresponding C5 epimer have been synthesized from the d-ribose-derived cyclic nitrone. (-)-Steviamine was found to be the first naturally occurring iminosugar that causes any inhibition of α-galactosaminidases. © 2010 American Chemical Society.
Horne G.,Summit Plc
Topics in Medicinal Chemistry | Year: 2014
Iminosugars, carbohydrate mimetics in which the endocyclic oxygen of the parent carbohydrate is replaced with nitrogen, are the most important class of carbohydrate mimetic reported to date with two marketed drugs and several in clinical development. Since their first isolation in the 1960s iminosugars have captured the imagination of both synthetic and medicinal chemists alike with recent therapeutic developments highlighting the need for improved routes of synthesis. The resurgence in the therapeutic application of iminosugars has arisen as a consequence of our growing understanding on the role that glycobiology plays in disease and development. There are myriad possible individual targets encompassing a range of therapeutic areas, all of which can potentially be addressed by iminosugars. This chapter presents the historcial development of this compound class before discussing some of the issues that iminosugars present as synthetic targets. The therapeutic potential of this class of compound with specific reference to the development of modulators of glucocerebrosidase activity is discussed. © Springer-Verlag Berlin Heidelberg 2014.
Weiss W.,University of North Texas Health Science Center |
Pulse M.,University of North Texas Health Science Center |
Vickers R.,Summit Plc
Antimicrobial Agents and Chemotherapy | Year: 2014
SMT19969 [2,2 ' -bis(4-pyridyl)3H,3'-H 5,5-bibenzimidazole] is a novel narrow-spectrum nonabsorbable antibiotic currently in development for the treatment of Clostridium difficile infection. The comparative activities of SMT19969 and vancomycin against nonepidemic and epidemic strains of C. difficile were studied in an established hamster model. Against nonepidemic (VA11) strains, the survival rates of SMT19969-treated animals ranged from 80% to 95%. Vancomycin exhibited 100% protection during treatment, with relapse observed starting on day 9 and 50% survival at day 20. At 50 mg/kg of body weight, SMT19969 administered orally once daily for 5 days provided full protection of treated animals on the dosing days and through day 12 against epidemic strains. Vancomycin also protected during the dosing interval, but apparent relapse occurred earlier, starting on day 11. SMT19969 exhibited excellent in vitro activity, with MICs of 0.25 (μg/ml for all isolates. The MICs for vancomycin were 2- to 4-fold higher at 0.5 to 1 μg/ml. All plasma sample concentrations of SMT19969 were below the limit of quantification (25 ng/ml) at all time points, consistent with the reported lack of bioavailability of the compound. Cecal concentrations were significantly above the MIC (ranging from 96 μg/ml to 172 μg/ml). Copyright © 2014 Weiss et al. This is an open access article distributed under the terms of the Creative Commons Attribtion 30 Unported license.
Danovi D.,University of Cambridge |
Falk A.,University of Cambridge |
Humphreys P.,University of Cambridge |
Vickers R.,Summit Plc |
And 3 more authors.
Biochemical Society Transactions | Year: 2010
The development of optimal culture methods for embryonic, tissue and cancer stem cells is a critical foundation for their application in drug screening. We previously described defined adherent culture conditions that enable expansion of human radial glia-like fetal NS (neural stem) cells as stable cell lines. Similar protocols proved effective in the establishment of tumour-initiating stem cell lines from the human brain tumour glioblastoma multiforme, which we termed GNS (glioma NS) cells. Others have also recently derived more primitive human NS cell lines with greater neuronal subtype differentiation potential than NS cells, which have similarities to the early neuroepithelium, named NES (neuroepithelial stem) cells. In the present paper, we discuss the utility of these cells for chemical screening, and describe methods for a simple high-content live-image-based platform. We report the effects of a panel of 160 kinase inhibitors (Inhibitor Select I and II; Calbiochem) on NES cells, identifying three inhibitors of ROCK (Rho-associated kinase) as promoting the expansion of NES cell cultures. For the GNS cells, we screened a panel of 1000 compounds and confirmed our previous finding of a cytotoxic effect of modulators of neurotransmitter signalling pathways. These studies provide a framework for future higher-throughput screens. ©The Authors.