Search Results

You searched for all publications:

with publication states 'Published (Approved)'

Search Again...

These results only include publications that have been reviewed and processed by Diamond Light Source. To also view papers that have not yet been processed click here.

You can use the folder icon under Actions to collate papers as required. You can then click on View Folder in the left-hand navigation to review and/or download your folder.

Exact matches
Related results

2 items found (0 items not approved), displaying all items.1

Instruments / Technical Area	Publication Details	Published	Actions
I04-Macromolecular Crystallography	New dual ATP-competitive inhibitors of bacterial DNA gyrase and topoisomerase IV active against ESKAPE pathogens Martina Durcik , Ákos Nyerges , Žiga Skok , Darja Gramec Skledar , Jurij Trontelj , Nace Zidar , Janez Ilaš , Anamarija Zega , Cristina D. Cruz , Päivi Tammela , Martin Welin , Yengo R. Kimbung , Dorota Focht , Ondřej Benek , Tamás Révész , Gábor Draskovits , Petra Éva Szili , Lejla Daruka , Csaba Pál , Danijel Kikelj , Lucija Peterlin Mašič , Tihomir Tomašič European Journal Of Medicinal Chemistry 213 DOI: 10.1016/j.ejmech.2021.113200 Diamond Proposal Number(s): [20028] Show Abstract ▼ Abstract: The rise in multidrug-resistant bacteria defines the need for identification of new antibacterial agents that are less prone to resistance acquisition. Compounds that simultaneously inhibit multiple bacterial targets are more likely to suppress the evolution of target-based resistance than monotargeting compounds. The structurally similar ATP binding sites of DNA gyrase and topoisomerase Ⅳ offer an opportunity to accomplish this goal. Here we present the design and structure-activity relationship analysis of balanced, low nanomolar inhibitors of bacterial DNA gyrase and topoisomerase IV that show potent antibacterial activities against the ESKAPE pathogens. For inhibitor 31c, a crystal structure in complex with Staphylococcus aureus DNA gyrase B was obtained that confirms the mode of action of these compounds. The best inhibitor, 31h, does not show any in vitro cytotoxicity and has excellent potency against Gram-positive (MICs: range, 0.0078–0.0625 μg/mL) and Gram-negative pathogens (MICs: range, 1–2 μg/mL). Furthermore, 31h inhibits GyrB mutants that can develop resistance to other drugs. Based on these data, we expect that structural derivatives of 31h will represent a step toward clinically efficacious multitargeting antimicrobials that are not impacted by existing antimicrobial resistance.	Mar 2021
I04-Macromolecular Crystallography	Exploring the chemical space of benzothiazole-based DNA gyrase B inhibitors Žiga Skok , Michaela Barančoková , Ondřej Benek , Cristina Durante Cruz , Päivi Tammela , Tihomir Tomašič , Nace Zidar , Lucija Peterlin Mašič , Anamarija Zega , Clare E. M. Stevenson , Julia E. A. Mundy , David M. Lawson , Anthony Maxwell , Danijel Kikelj , Janez Ilaš Acs Medicinal Chemistry Letters DOI: 10.1021/acsmedchemlett.0c00416 Diamond Proposal Number(s): [18565] Open Access Show Abstract ▼ Abstract: We designed and synthesized a series of inhibitors of the bacterial enzymes DNA gyrase and DNA topoisomerase IV, based on our recently published benzothiazole-based inhibitor bearing an oxalyl moiety. To improve the antibacterial activity and retain potent enzymatic activity, we systematically explored the chemical space. Several strategies of modification were followed: varying substituents on the pyrrole carboxamide moiety, alteration of the central scaffold, including variation of substitution position and, most importantly, modification of the oxalyl moiety. Compounds with acidic, basic, and neutral properties were synthesized. To understand the mechanism of action and binding mode, we have obtained a crystal structure of compound 16a, bearing a primary amino group, in complex with the N-terminal domain of E. coli gyrase B (24 kDa) (PDB: 6YD9). Compound 15a, with a low molecular weight of 383 Da, potent inhibitory activity on E. coli gyrase (IC50 = 9.5 nM), potent antibacterial activity on E. faecalis (MIC = 3.13 μM), and efflux impaired E. coli strain (MIC = 0.78 μM), is an important contribution for the development of novel gyrase and topoisomerase IV inhibitors in Gram-negative bacteria.	Oct 2020

Publications Database

Search Results

You searched for all publications:

Search Again...

Subject Areas (check all that apply) select all

Instruments used to collect data (check all that apply) select all

Collaborations involved (check all that apply) select all

Diamond Offline Facilities used

Relevant Technical Areas (check all that apply) select all

Menu for Anonymous User