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A Chemical Disruptor of the ClpX Chaperone Complex Attenuates the Virulence of Multidrug‐Resistant Staphylococcus aureus
Author(s) -
Fetzer Christian,
Korotkov Vadim S.,
Thänert Robert,
Lee Kyu Myung,
Neuenschwander Martin,
von Kries Jens Peter,
Medina Eva,
Sieber Stephan A.
Publication year - 2017
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201708454
Subject(s) - virulence , chaperone (clinical) , biology , staphylococcus aureus , transcriptome , proteome , microbiology and biotechnology , regulator , protease , bacteria , biochemistry , genetics , gene expression , gene , enzyme , medicine , pathology
The Staphylococcus aureus ClpXP protease is an important regulator of cell homeostasis and virulence. We utilized a high‐throughput screen against the ClpXP complex and identified a specific inhibitor of the ClpX chaperone that disrupts its oligomeric state. Synthesis of 34 derivatives revealed that the molecular scaffold is restrictive for diversification, with only minor changes tolerated. Subsequent analysis of the most active compound 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. Although these partially matched the pattern of ClpX knockout cells, further depletion of toxins was observed, leading to the intriguing perspective that additional virulence pathways may be directly or indirectly addressed by the small molecule.