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Chemical Biology News

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By Lloyd Czaplewski, Nov 8 2012 02:24PM

Published in Antimicrobial Agents & Chemotherapy by Neil R. Stokes, Nicola Baker, James M. Bennett, Joanne Berry, Ian Collins, Lloyd G. Czaplewski, Alastair Logan, Rebecca Macdonald, Leanne MacLeod, Hilary Peasley, Jeffrey P. Mitchell, Narendra Nayal, Anju Yadav, Anil Srivastava and David J. Haydon

The bacterial cell division protein, FtsZ, is an attractive target for small-molecule antibacterial drug discovery. Derivatives of 3-methoxybenzamide, including compound PC190723, have previously been reported as potent and selective anti-staphylococcal agents, which exert their effect through the disruption of intracellular FtsZ function. Here, we report the further optimization of 3-methoxybenzamide derivatives towards a drug candidate. The in vitro and in vivo characterization of a more advanced lead compound, designated Compound 1, is described. Compound 1 was potently antibacterial, with an average MIC of 0.12 μg/mL against all staphylococcal species, including methicillin- and multidrug-resistant Staphylococcus aureus and S. epidermidis. Compound 1 inhibited a S. aureus strain carrying the G196A mutation in FtsZ, which confers resistance to PC190723. Like PC190723, Compound 1 acted on whole bacterial cells by blocking cytokinesis. No interactions between Compound 1 and a diverse panel of antibiotics were measured in checkerboard experiments. Compound 1 displayed suitable in vitro pharmaceutical properties and a favorable in vivo pharmacokinetic profile following intravenous and oral administration, with a calculated bioavailability of 82.0% in mice. Compound 1 demonstrated efficacy in the murine S. aureus systemic model of infection and caused a significant decrease in bacterial load in the thigh infection model. A greater reduction in the number of S. aureus cells recovered from infected thighs, equivalent to 3.68 log versus controls, was achieved using a succinate pro-drug of Compound 1, designated Compound 2. In summary, optimized derivatives of 3-methoxybenzamide may yield a first-in-class FtsZ inhibitor for the treatment of antibiotic-resistant staphylococcal infections.

By Lloyd Czaplewski, Nov 8 2012 12:07PM

CBV's founder Lloyd Czaplewski has been appointed as an Honorary Senior Research Fellow in the School of Immunity & Infection within the College of Medical & Dental Sciences at the University of Birmingham, U.K.

Recently Dr Czaplewski located his antibacterial company, Abgentis Limited, the antibiotic re-engineering Company, at the University of Birmingham Research Park. This Honorary position will provide exciting opportunities to develop collaborative projects that build on the excellent platforms developed by Abgentis and on Birmingham's world-leading research and increasingly translational focus on microbiology and infection.

By Lloyd Czaplewski, May 19 2012 09:08AM

The Royal Society of Chemistry's Designing Multi-Target Drugs provides a valuable resource for those interested in creating novel therapies for complex diseases. The chapter on anti-bacterial DNA supercoiling inhibitors "Ethyl Urea Inhibitors of the Bacterial Type II Topoisomerases DNA Gyrase (GyrB) and Topoisomerase IV (ParE)" by Stephen P. East, Lloyd G. Czaplewski and David J. Haydon will be particularly useful for those involved in or starting out in antibacterial drug discovery


By Lloyd Czaplewski, May 1 2012 08:28AM

The £180 million Biomedical Catalyst fund will see the Medical Research Council and the Technology Strategy Board working together to provide responsive and effective support for the best life science opportunities arising in the UK.

Targeting SMEs and academics working independently or in collaborations, the Catalyst will provide critical funding for feasibility studies as well as early and later stage development activities.

Chemical Biology Ventures can provide value-adding consultancy through the application process and project delivery. Please contact us to discuss how we can work with you to maximise your chance of success.


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