Dr Christian Fetzer, Technical University of Munich; Dr Vadim Krotokov, Technical University of Munich; Prof. Stephan Sieber, Technical University of Munich
Staphylococcus aureus is a gram-positive pathogen responsible for devastating infections of e.g. lungs, skin and bones. A diverse arsenal of virulence factors or toxins facilitates the establishment of infection by enabling the bacterium to thwart the immune response and survive within the host. The treatment and prevention of staphylococcal infections with classical antibiotics has become challenging due to the increasing prevalence of multiresistant S. aureus strains such as methicillin-resistant S. aureus (MRSA). Thus, alternative strategies that target bacterial virulence rather than viability have been proposed.
In contrast to conventional antibiotics, antivirulence compounds do not interfere with the pathogens’ survival but rather disarm the bacteria, therefore supporting the immune system without direct selective pressure. In S. aureus the ClpXP protease is a global regulator of virulence factor production. Novel small molecules bind to the protease and lead to its disruption. This impairs the pathogen’s ability to produce toxins without interfering with its viability. A high-throughput screen against the S. aureus ClpXP protease revealed a set of potent small molecule inhibitors. In order to gain an insight into structure-activity relationship, a small library of >30 compounds was synthesized. Mass-spectrometry based analysis revealed simultaneous inhibition of several toxins. The compounds showed high plasma stability in in vitro assays. Further optimization is needed to increase the therapeutic window, however, derivatives with low toxicity have already been identified and will be tested in a mouse infection model.
- New pharmacological anti-virulence strategies
- Available as monotherapy or as combination therapy with antibiotics
- Applicable for following areas: bacterial virulence and leukemia
Proof of concept in vitro. In vivo experiments are currently being performed.
PCT patent application filed in 2017.
C. Fetzer, V. S. Korotkov, R. Thänert, K. M. Lee, M. Neuenschwander, J. P. von Kries, E. Medina, S. A. Sieber, „A Chemical Disruptor of the ClpX Chaperone Complex Attenuates the Virulence of Multidrug-Resistant Staphylococcus aureus“, Angew. Chem. Int. Ed. 2017, 56, 15746.
A high-throughput screen against the ClpXP protease revealed the first non-covalent inhibitors of the chaperone ClpX. Binding of the inhibitors induces disruption of the ClpX hexamer and even of the whole ClpXP proteolytic complex. Treatment of Staphylococcus aureus with the compounds leads to a global down-regulation of a plethora of secreted virulence factors.