Dataset Information

A Chemical Disruptor of the ClpX Chaperone Complex Attenuates Multiresistant Staphylococcus aureus Virulence

ABSTRACT: The Staphylococcus aureus ClpXP protease is an important regulator of cell homeostasis and virulence. Here we utilize a high-throughput screen against the ClpXP complex and identify 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 via a novel MS-based assay platform. Transcriptome and whole proteome studies further confirmed the global reduction of virulence and unraveled characteristic signatures of protein expression in 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.

INSTRUMENT(S): LTQ Orbitrap XL, Orbitrap Fusion, Q Exactive

ORGANISM(S): Staphylococcus Aureus

SUBMITTER: Christian Fetzer

LAB HEAD: Stephan A Sieber

PROVIDER: PXD007259 | Pride | 2017-09-14

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	20160125_CF_Extraz_10uM-AV334_1.raw	Raw
	20160125_CF_Extraz_10uM-AV334_2.raw	Raw
	20160125_CF_Extraz_10uM-AV334_3.raw	Raw
	20160219_Extraz3_Replikat_3.raw	Raw
	20160219_Extraz3_Replikat_3uL_1.raw	Raw

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A Chemical Disruptor of the ClpX Chaperone Complex Attenuates the Virulence of Multidrug-Resistant Staphylococcus aureus.

Fetzer Christian C Korotkov Vadim S VS Thänert Robert R Lee Kyu Myung KM Neuenschwander Martin M von Kries Jens Peter JP Medina Eva E Sieber Stephan A SA

Angewandte Chemie (International ed. in English) 20171012 49

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 ...[more]

PMID: 28906057

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