Design and synthesis of novel clostridial collagenase inhibitors
Clostridia represent a family of ubiquitously occurring Gram-positive bacteria comprising perilous pathogens causing serious infectious diseases. The high lethality of these bacteria is related to collagenases which are crucial for clostridial virulence, given their critical role in colonisation and evasion of host immune defence, acquisition of nutrients, facilitation of dissemination, or tissue damage during infection. The inhibition of these extracellular collagenases is conceptually attractive, as it does not attack the pathogen directly but rather blocks the colonisation and infiltration of the host by the clostridia. Targeting extracellular enzymes has the added benefit that inhibitors do not need to cross the bacterial cell wall, which has been challenging in many cases. Clostridial collagenases are zinc metalloproteinases with a multi-domain organisation, homologues of which are also found in many bacilli. Our group was the first who published compounds showing not only a highly potent inhibition of clostridial and bacillal collagenases (ColH IC50 in nM range) but also a strong selectivity over human MMPs.
- Drug Design and Optimization- Prof. Dr. Anna K. H. Hirsch
HZI - Helmholtz Centre for Infection Research