CHEMICAL DISRUPTION OF CLPX INHIBITS MULTIRESISTANT S. AUREUS
Staphylococcus aureus is a gram-positive pathogen responsible for devasting infections of lung, skin and bones. With the onset of multiresistant S. aureus (MRSA) their treatment and prevention becomes challenging with classical antibiotics. S. aureus virulence is controlled by a complex network involving quorum sensing mediated by the accessory gene regulator (agr) system. It expresses autoinducing peptides that sense bacterial growth and initiate the production of toxins. Caseinolytic protease (ClpP) associates with chaperones such as ClpX to form a complex that recognize and unfold substrate proteins and thereby strongly influence the agr-dependent toxin expression. Several specific ClpP inhibitors have been reported foremost beta-lactones attenuating S. aureus virulence, but their facile ester bond limited pharmacological apllications. ClpX represents a crucial new target for anti-virulence strategies, however, only little is known about selective inhibitors.
A high-throughput screen against the ClpXP complex was performed and identiﬁed 334 as a specific inhibitor of the ClpX chaperone that disrupts its oligomeric state. Subsequent analysis revealed strong attenuation of S. aureus toxin production, which was quantiﬁed with a customized MS-based assay platform. Transcriptome and whole-proteome studies further conﬁrmed the global reduction of virulence and revealed characteristic signatures of protein expression in the compound-treated cells. Synthesis of 34 derivatives revealed that the molecular scaffold is restrictive for diversiﬁcation, with only minor changes tolerated. Compound 367 was identiﬁed showing similar potency but reduced toxicity against A549 lung cancer cells. Furthermore, compound 367 was successfully used in a zebrafish infection model resulting in the ﬁrst in vivo proof of concept.
- New pharmacological anti-virulence strategies
- Available as mono therapy or as combination therapy with antibiotics
- Applicable for following areas: bacterial virulence and leukemia
Proof of concept in vitro & in vivo.
Further in vivo experiments (toxicology and in mice) are currently being performed.
Fetzer, C., Korotkov, V.S., Thänert, R., Lee, K.M., Neuenschwander, M., von Kries, J.P., Medina, E., Sieber, S.A., „A Chemical Disruptor of the ClpX Chaperone Complex Attenuates the Virulence of Multidrug-Resistant Staphylococcus aureus“, Angew. Chem. Int. Edit.