By lloyd czaplewski, Apr 17 2017 10:56AM
GYR12, Abgentis' lead novobiocin analogue, in combination with colistin, is effective against colistin-resistant strains of E. coli, K. pneumoniae and A. baumannii. Sub-microgramme per ml concentrations of GYR12 with 2 ug/ml of colistin kill strains that are resistant to either compound alone. Colistin-resistant (MIC >256 ug/ml colistin) can be fully resensitised and killed.
The GYR12/colistin combination provides a broad-spectrum opportunity which Abgentisis evaluating through detailed preclinical studies.
By lloyd czaplewski, Nov 20 2013 7:20PM
Novel antibacterial programmes developed under the leadership of Lloyd Czaplewski when he was at Prolysis and Biota Europe are being published.
Stokes NR, Thomaides-Brears HB, Barker S, Bennett JM, Berry J, Collins I, Czaplewski LG, Gamble V, Lancett P, Logan A, Lunniss CJ, Peasley H, Pommier S, Price D, Smee C, Haydon DJ.
Antimicrob Agents Chemother. 2013 Dec;57(12):5977-86
The type II topoisomerases DNA gyrase (GyrA/GyrB) and topoisomerase IV (ParC/ParE) are well-validated targets for antibacterial drug discovery. Because of their structural and functional homology, these enzymes are amenable to dual targeting by a single ligand. In this study, two novel benzothiazole ethyl urea-based small molecules, designated compound A and compound B, were evaluated for their biochemical, antibacterial, and pharmacokinetic properties. The two compounds inhibited the ATPase activity of GyrB and ParE with 50% inhibitory concentrations of <0.1 μg/ml. Prevention of DNA supercoiling by DNA gyrase was also observed. Both compounds potently inhibited the growth of a range of bacterial organisms, including staphylococci, streptococci, enterococci, Clostridium difficile, and selected Gram-negative respiratory pathogens. MIC90s against clinical isolates ranged from 0.015 μg/ml for Streptococcus pneumoniae to 0.25 μg/ml for Staphylococcus aureus. No cross-resistance with common drug resistance phenotypes was observed. In addition, no synergistic or antagonistic interactions between compound A or compound B and other antibiotics, including the topoisomerase inhibitors novobiocin and levofloxacin, were detected in checkerboard experiments. The frequencies of spontaneous resistance for S. aureus were <2.3 × 10(-10) with compound A and <5.8 × 10(-11) with compound B at concentrations equivalent to 8× the MICs. These values indicate a multitargeting mechanism of action. The pharmacokinetic properties of both compounds were profiled in rats. Following intravenous administration, compound B showed approximately 3-fold improvement over compound A in terms of both clearance and the area under the concentration-time curve. The measured oral bioavailability of compound B was 47.7%.
By lloyd czaplewski, Aug 22 2013 6:42PM
Antibiotic Action, supported by the BSAC, th Medical Research Council, The Wellcome Trust and BBSRC, invited fifty international experts from academia, science, medicine and industry consider what lessons can be learnt from the last 40-years to aid the discovery and development of new antibacterial agents. In a ground breaking event speakers examined issues such as why interesting antibiotic molecules were not developed, to difficulties in developing antibiotic drugs for Gram negative infections.
A summary of the meeting can be found at http://antibiotic-action.com/2013/08/21/lessons-to-be-learnt-from-pharma-about-discovery-and-development-of-new-antibacterial-drugs-report-now-available/
By lloyd czaplewski, Nov 8 2012 2:22PM
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 12:11PM
Abgentis' 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 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.
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