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Stokes N.R.,Biota Europe Ltd. | Baker N.,Biota Europe Ltd. | Baker N.,London School of Hygiene and Tropical Medicine | Bennett J.M.,Biota Europe Ltd. | And 14 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2013

The bacterial cell division protein FtsZ is an attractive target for small-molecule antibacterial drug discovery. Derivatives of 3-methoxybenzamide, including compound PC190723, have been reported to be potent and selective antistaphylococcal agents which exert their effects 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 Staphylococcus epidermidis. Compound 1 inhibited an 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 a murine model of systemic S. aureus infection and caused a significant decrease in the 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 units, than in those recovered from controls was achieved using a succinate prodrug of compound 1, which was 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. Copyright © 2013, American Society for Microbiology. All Rights Reserved.


Yule I.A.,University of Leeds | Czaplewski L.G.,Biota Europe Ltd | Pommier S.,Biota Europe Ltd | Davies D.T.,Biota Europe Ltd | And 2 more authors.
European Journal of Medicinal Chemistry | Year: 2014

The development of antibacterial drugs based on novel chemotypes is essential to the future management of serious drug resistant infections. We herein report the design, synthesis and SAR of a novel series of N-ethylurea inhibitors based on a pyridine-3-carboxamide scaffold targeting the ATPase sub-unit of DNA gyrase. Consideration of structural aspects of the GyrB ATPase site has aided the development of this series resulting in derivatives that demonstrate excellent enzyme inhibitory activity coupled to potent Gram positive antibacterial efficacy. © 2014 Elsevier Masson SAS. All rights reserved.


Adams D.W.,Northumbria University | Wu L.J.,Northumbria University | Czaplewski L.G.,Biota Europe Ltd | Errington J.,Northumbria University
Molecular Microbiology | Year: 2011

Cell division in almost all bacteria is orchestrated by the essential tubulin homologue FtsZ, which assembles into a ring-like structure and acts as a scaffold for the division machinery. Division was recently validated as an important target for antibiotics by the demonstration that low-molecular-weight inhibitors of FtsZ, called benzamides, can cure mice infected with Staphylococcus aureus. In treated cells of Bacillus subtilis we show that FtsZ assembles into foci throughout the cell, including abnormal locations at the cell poles and over the nucleoid. These foci are not inactive aggregates because they remain dynamic, turning over almost as rapidly as untreated polymers. Remarkably, although division is completely blocked, the foci efficiently recruit division proteins that normally co-assemble with FtsZ. However, they show no affinity for components of the Min or Nucleoid occlusion systems. In vitro, the benzamides strongly promote the polymerization of FtsZ, into hyperstable polymers, which are highly curved. Importantly, even at low concentrations, benzamides transform the structure of the Z ring, resulting in abnormal helical cell division events. We propose that benzamides act principally by promoting an FtsZ protomer conformation that is incompatible with a higher-order level of assembly needed to make a division ring. © 2011 Blackwell Publishing Ltd.


Patent
Biota Europe Ltd | Date: 2013-03-21

The present invention provides a compound of the following formula, salts, racemates, diastereomers, enantiomers, esters, carbamates, phosphates, sulfates, deuterated forms and prodrugs thereof. Also provided is the use of these compounds as antibacterials, compositions comprising them and processes for their manufacture.


Patent
Biota Europe Ltd | Date: 2015-02-03

The present disclosure relates to a novel combination of compounds, their use as antibacterials, compositions comprising them and methods for treating or preventing bacterial infections, more particularly, bacterial infections caused by Gram-negative pathogens and/or drug resistant Gram-negative bacteria.


Patent
Biota Europe Ltd | Date: 2011-06-07

Compounds of formula (I) have antibacterial activity: wherein: m is 0 or 1; Q is hydrogen or cyclopropyl; Alk is an optionally substituted, divalent C_(1)-C_(6 )alkylene, alkenylene or alkynylene radical which may contain an ether (O), thioether (S) or amino (NR) link, wherein R is hydrogen, CN or C_(1)-C_(3 )alkyl; X is C(O)NR_(6), S(O)NR_(6), C(O)O or S(O)O wherein R_(6 )is hydrogen, optionally substituted C_(1)-C_(6 )alkyl, C_(2)-C_(6 )alkenyl, C_(2)-C_(6 )alkynyl, -Cyc, or (C_(1)-C_(3 )alkyl)-Cyc wherein Cyc is optionally substituted monocyclic carbocyclic or heterocyclic having 3-7 ring atoms; Z is N or CH, or CF; R_(2 )and R_(3 )are as defined in the description.


Patent
Biota Europe Ltd. | Date: 2011-10-07

The present invention provides a compound of the following formula and salts thereof: Also provided is the use of these compounds as antibacterials, compositions comprising them and processes for their manufacture.


Patent
Biota Europe Ltd | Date: 2012-12-21

The present invention provides a compound of the following formula, racemates, enantiomers and salts thereof. Also provided is the use of these compounds as antibacterials, compositions comprising them and processes for their manufacture.


Patent
Biota Europe Ltd | Date: 2011-06-07

Compounds of formula (I) have antibacterial activity: wherein: m is 0 or 1; Q is hydrogen or cyclopropyl; Alk is an optionally substituted, divalent C_(1)-C_(6 )alkylene, alkenylene or alkynylene radical which may contain an ether (O), thioether (S) or amino (NR) link, wherein R is hydrogen, CN or C_(1)-C_(3 )alkyl; X is C(O)NR_(6), S(O)NR_(6), C(O)O or S(O)O wherein R_(6 )is hydrogen, optionally substituted C_(1)-C_(6 )alkyl, C_(2)-C_(6 )alkenyl, C_(2)-C_(6 )alkynyl, -Cyc, or (C_(1)-C_(3 )alkyl)-Cyc wherein Cyc is optionally substituted monocyclic carbocyclic or heterocyclic having 3-7 ring atoms; Z is N; R_(2 )and R_(3 )are as defined in the description.


Patent
Biota Europe Ltd. | Date: 2013-03-21

The present invention provides a compound of the following formula, salts, racemates, diastereomers, enantiomers, esters, carbamates, phosphates, sulfates, deuterated forms and prodrugs thereof. Also provided is the use of these compounds as antibacterials, compositions comprising them and processes for their manufacture.

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