Towards photopharmacological antimicrobial chemotherapy using photoswitchable amidohydrolase inhibitors

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Title: Towards photopharmacological antimicrobial chemotherapy using photoswitchable amidohydrolase inhibitors
Authors: Weston, CE
Kraemer, A
Colin, F
Yildiz, Ö
Baud, MG
Meyer-Almes, FJ
Fuchter, MJ
Item Type: Journal Article
Abstract: Photopharmacological agents exhibit light-dependent biological activity and may have potential in the development of new antimicrobial agents/modalities. Amidohydrolase enzymes homologous to the well known human histone deacetylases (HDACs) are present in bacteria, including resistant organisms responsible for a significant number of hospital acquired infections and deaths. We report photopharmacological inhibitors of these enzymes, using two classes of photoswitch embedded in the inhibitor pharmacophore: azobenzenes and arylazopyrazoles. While both classes of inhibitor show excellent inhibitory activity (nM IC50 values) of the target enzymes and promising differential activity of the switchable E- and Z-isomeric forms, the arylazopyrazoles exhibit better intrinsic photoswitch performance (more complete switching, longer thermal lifetime of the Z‑isomer). We also report protein-ligand crystal structures of the E-isomers of both an azobenzene and an arylazopyrazole inhibitor, bound to bacterial histone deacetylase-like amidohydrolases (HDAHs). These structures not only uncover interactions important for inhibitor binding, but also reveal conformational differences between the two photoswitch inhibitor classes. As such, our data may pave the way for the design of improved photopharmacological agents targeting the HDAC superfamily.
Issue Date: 18-Oct-2016
Date of Acceptance: 1-Oct-2016
URI: http://hdl.handle.net/10044/1/42053
DOI: https://dx.doi.org/10.1021/acsinfecdis.6b00148
ISSN: 2373-8227
Publisher: American Chemical Society
Start Page: 152
End Page: 161
Journal / Book Title: ACS Infectious Diseases
Volume: 3
Issue: 2
Copyright Statement: © 2016 American Chemical Society. This document is the Accepted Manuscript version of a Published Work that appeared in final form in ACS Infectious Diseases, after peer review and technical editing by the publisher. To access the final edited and published work see http://dx.doi.org/10.1021/acsinfecdis.6b00148.
Keywords: Pseudomonas aeruginosa
arylazopyrazole
azobenzene
histone deacetylase
photopharmacology
Publication Status: Published
Appears in Collections:Chemistry
Faculty of Natural Sciences



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