Phosphonate as a Stable Zinc-Binding Group for "Pathoblocker" Inhibitors of Clostridial Collagenase H (ColH).

Katrin Voos,Christian Ducho,Rolf Müller,Hans Brandstetter,Alaa Alhayek,Anna K H Hirsch,Rolf W Hartmann,Jörg Haupenthal,Anastasia Andreas,Esther Schönauer

doi:10.1002/cmdc.202000994

Abstract

Microbial infections are a significant threat to public health, and resistance is on the rise, so new antibiotics with novel modes of action are urgently needed. The extracellular zinc metalloprotease collagenase H (ColH) from Clostridium histolyticum is a virulence factor that catalyses tissue damage, leading to improved host invasion and colonisation. Besides the major role of ColH in pathogenicity, its extracellular localisation makes it a highly attractive target for the development of new antivirulence agents. Previously, we had found that a highly selective and potent thiol prodrug (with a hydrolytically cleavable thiocarbamate unit) provided efficient ColH inhibition. We now report the synthesis and biological evaluation of a range of zinc‐binding group (ZBG) variants of this thiol‐derived inhibitor, with the mercapto unit being replaced by other zinc ligands. Among these, an analogue with a phosphonate motif as ZBG showed promising activity against ColH, an improved selectivity profile, and significantly higher stability than the thiol reference compound, thus making it an attractive candidate for future drug development.

Highlights

Due to emerging resistances against established antibacterial agents, the treatment of bacterial infections might be thrown back to a state similar to the pre-antibiotic era
We demonstrated that the linker unit in structures of type 5 a, that is, the motif connecting the aromatic moiety and the thiol zinc-binding group (ZBG), can be varied
Succinic acid derivative 10 is a notable exception to the aforementioned design principle as it was the higher homologue of malonic acid derivative 9 and the acid

Summary

Introduction

Due to emerging resistances against established antibacterial agents, the treatment of bacterial infections might be thrown back to a state similar to the pre-antibiotic era. Brandstetter Department of Biosciences and Christian Doppler Laboratory for Innovative Tools for Biosimilar Characterization Division of Structural Biology, University of Salzburg Billrothstrasse 11, 5020 Salzburg (Austria). Müller Department of Microbial Natural Products Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) Helmholtz Centre for Infection Research (HZI) Campus E8 1, 66123 Saarbrücken (Germany)

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