Open AccessDiscovery and Characterization of Synthesized and FDA-Approved Inhibitors of Clostridial and Bacillary Collagenases
Author(s) -
Alaa Alhayek,
Ahmed S. Abdelsamie,
Esther Schönauer,
Virgyl Camberlein,
Evelyn Hutterer,
Gernot Posselt,
Jamil Serwanja,
Constantin Blöchl,
Christian G. Huber,
Jörg Haupenthal,
Hans Brandstetter,
Silja Weßler,
Anna K. H. Hirsch
Publication year - 2022
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.2c00785
Subject(s) - collagenase , chemistry , bacillus cereus , microbiology and biotechnology , repurposing , proteases , in vitro , staphylococcus aureus , pharmacology , biochemistry , enzyme , biology , bacteria , ecology , genetics
In view of the worldwide antimicrobial resistance (AMR) threat, new bacterial targets and anti-infective agents are needed. Since important roles in bacterial pathogenesis have been demonstrated for the collagenase H and G (ColH and ColG) from Clostridium histolyticum , collagenase Q1 and A (ColQ1 and ColA) from Bacillus cereus represent attractive antivirulence targets. Furthermore, repurposing FDA-approved drugs may assist to tackle the AMR crisis and was addressed in this work. Here, we report on the discovery of two potent and chemically stable bacterial collagenase inhibitors: synthesized and FDA-approved diphosphonates and hydroxamates. Both classes showed high in vitro activity against the clostridial and bacillary collagenases. The potent diphosphonates reduced B. cereus -mediated detachment and death of cells and Galleria mellonella larvae. The hydroxamates were also tested in a similar manner; they did not have an effect in infection models. This might be due to their fast binding kinetics to bacterial collagenases.