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High-throughput crystallography reveals boron-containing inhibitors of a Penicillin-binding protein with di- and tricovalent binding modes

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Newman, Hector, Krajnc, Alen, Bellini, Dom, Eyermann, Charles J., Boyle, Grant A., Paterson, Neil G., McAuley, Katherine E., Lesniak, Robert, Gangar, Mukesh, von Delft, Frank, Brem, Jürgen, Chibale, Kelly, Schofield, Christopher J. and Dowson, Christopher G. (2021) High-throughput crystallography reveals boron-containing inhibitors of a Penicillin-binding protein with di- and tricovalent binding modes. Journal of Medicinal Chemistry, 64 (15). pp. 11379-11394. doi:10.1021/acs.jmedchem.1c00717

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Official URL: https://doi.org/10.1021/acs.jmedchem.1c00717

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Abstract

The effectiveness of β-lactam antibiotics is increasingly compromised by β-lactamases. Boron-containing inhibitors are potent serine-β-lactamase inhibitors, but the interactions of boron-based compounds with the penicillin-binding protein (PBP) β-lactam targets have not been extensively studied. We used high-throughput X-ray crystallography to explore reactions of a boron-containing fragment set with the PBP3 (PaPBP3). Multiple crystal structures reveal that boronic acids react with PBPs to give tricovalently linked complexes bonded to Ser294, Ser349, and Lys484 of PaPBP3; benzoxaboroles react with PaPBP3 via reaction with two nucleophilic serines (Ser294 and Ser349) to give dicovalently linked complexes; and vaborbactam reacts to give a monocovalently linked complex. Modifications of the benzoxaborole scaffold resulted in a moderately potent inhibition of PaPBP3, though no antibacterial activity was observed. Overall, the results further evidence the potential for the development of new classes of boron-based antibiotics, which are not compromised by β-lactamase-driven resistance.

Item Type: Journal Article
Subjects: Q Science > QD Chemistry
Q Science > QP Physiology
R Medicine > RM Therapeutics. Pharmacology
R Medicine > RS Pharmacy and materia medica
Divisions: Faculty of Science > Life Sciences (2010- )
SWORD Depositor: Library Publications Router
Library of Congress Subject Headings (LCSH): Beta lactam antibiotics , Beta lactam antibiotics -- Structure-activity relationships , Beta lactam antibiotics -- Synthesis, Beta lactamases, Beta lactamases -- Inhibitors , Protein binding, Boron -- Inhibitors, X-ray crystallography
Journal or Publication Title: Journal of Medicinal Chemistry
Publisher: American Chemical Society
ISSN: 0022-2623
Official Date: 12 August 2021
Dates:
DateEvent
12 August 2021Published
31 July 2021Available
13 July 2021Accepted
Volume: 64
Number: 15
Page Range: pp. 11379-11394
DOI: 10.1021/acs.jmedchem.1c00717
Status: Peer Reviewed
Publication Status: Published
Access rights to Published version: Open Access
RIOXX Funder/Project Grant:
Project/Grant IDRIOXX Funder NameFunder ID
MR/P007503/1Newton Fundhttp://dx.doi.org/10.13039/100010897
STU0212University of Warwickhttp://dx.doi.org/10.13039/501100000741
STU0212Diamond Light Sourcehttp://dx.doi.org/10.13039/100011889
GCRFNG\100347Global Challenges Research FundUNSPECIFIED
MR/N002679/1[MRC] Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
MR/P007503/1[MRC] Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
106244/Z/14/ZWellcome Trusthttp://dx.doi.org/10.13039/100010269
UNSPECIFIEDNovartis Stiftung für Medizinisch-Biologische Forschunghttp://dx.doi.org/10.13039/501100004784
UNSPECIFIEDSouth African Medical Research Councilhttp://dx.doi.org/10.13039/501100001322
UNSPECIFIEDNational Research Foundationhttp://dx.doi.org/10.13039/501100001321
UNSPECIFIEDCancer Research UKhttp://dx.doi.org/10.13039/501100000289
UNSPECIFIEDPublic Scholarship, Development, Disability and Maintenance Fund of the Republic of Sloveniahttps://www.srips-rs.si/en/scholarships
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