Discovery and Characterization of Synthesized and FDA-Approved Inhibitors of Clostridial and Bacillary Collagenases

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.