Tackling pseudomonas aeruginosa virulence by a hydroxamic acid-absed LasB inhibitor

Kany, A. M., Sikandar, A., Yahiaoui, S., Haupenthal, J., Walter, I., Empting, M., Köhnke, J. and Hartmann, R. W. (2018) Tackling pseudomonas aeruginosa virulence by a hydroxamic acid-absed LasB inhibitor. ACS Chemical Biology, 13(9), pp. 2449-2455. (doi: 10.1021/acschembio.8b00257) (PMID:30088919)

Abstract

In search of novel antibiotics to combat the challenging spread of resistant pathogens, bacterial proteases represent promising targets for pathoblocker development. A common motif for protease inhibitors is the hydroxamic acid function, yet this group has often been related to unspecific inhibition of various metalloproteases. In this work, the inhibition of LasB, a harmful zinc metalloprotease secreted by Pseudomonas aeruginosa, through a hydroxamate derivative is described. The present inhibitor was developed based on a recently reported, highly selective thiol scaffold. Using X-ray crystallography, the lack of inhibition of a range of human matrix metalloproteases could be attributed to a distinct binding mode sparing the S1′ pocket. The inhibitor was shown to restore the effect of the antimicrobial peptide LL-37, decrease the formation of P. aeruginosa biofilm and, for the first time for a LasB inhibitor, reduce the release of extracellular DNA. Hence, it is capable of disrupting several important bacterial resistance mechanisms. These results highlight the potential of protease inhibitors to fight bacterial infections and point out the possibility to achieve selective inhibition even with a strong zinc anchor.

• Item Type: Articles
• Additional Information: J.K. acknowledges the DFG for an Emmy−Noether Fellowship (KO 4116/3-1).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Koehnke, Professor Jesko
• Authors: Kany, A. M., Sikandar, A., Yahiaoui, S., Haupenthal, J., Walter, I., Empting, M., Köhnke, J., and Hartmann, R. W.
• College/School: College of Science and Engineering > School of Chemistry
• Journal Name: ACS Chemical Biology
• Publisher: American Chemical Society
• ISSN: 1554-8929
• ISSN (Online): 1554-8937
• Published Online: 08 August 2018
• Copyright Holders: Copyright © 2018 American Chemical Society
• First Published: First published in ACS Chemical Biology 13(9):2449-2455
• Publisher Policy: Reproduced in accordance with the copyright policy of the publisher