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Methicillin-resistant Staphylococcus aureus (MRSA) causes severe infections with only few effective antibiotic therapies currently available. To approach this challenge, chemical entities with a novel and resistance-free mode of action are desperately needed. Here, we introduce a new hydroxyamide compound that effectively reduces the expression of devastating toxins in various S. aureus and MRSA strains. The molecular mechanism was investigated by transcriptome analysis as well as by affinity-based protein profiling. Down-regulation of several pathogenesis associated genes suggested the inhibition of a central virulence-related pathway. Mass spectrometry-based chemical proteomics revealed putative molecular targets. Systemic treatment with the hydroxyamide showed significant reduction of abscess sizes in a MRSA mouse skin infection model. The absence of resistance development in vitro further underlines the finding that targeting virulence could lead to prolonged therapeutic options in comparison to antibiotics that directly address bacterial survival. [ABSTRACT FROM AUTHOR]

Methicillin-resistant Staphylococcus aureus (MRSA) causes severe infections with only few effective antibiotic therapies currently available. To approach this challenge, chemical entities with a novel and resistance-free mode of action are desperately needed. Here, we introduce a new hydroxyamide compound that effectively reduces the expression of devastating toxins in various S. aureus and MRSA strains. The molecular mechanism was investigated by transcriptome analysis as well as by affinity-based protein profiling. Down-regulation of several pathogenesis associated genes suggested the inhibition of a central virulence-related pathway. Mass spectrometry-based chemical proteomics revealed putative molecular targets. Systemic treatment with the hydroxyamide showed significant reduction of abscess sizes in a MRSA mouse skin infection model. The absence of resistance development in vitro further underlines the finding that targeting virulence could lead to prolonged therapeutic options in comparison to antibiotics that directly address bacterial survival., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Caseinolytic protease P (ClpP) is an important regulator of Staphylococcus aureus pathogenesis. A high-throughput screening for inhibitors of ClpP peptidase activity led to the identification of the first non-covalent binder for this enzyme class. Co-crystallization of the small molecule with S. aureus ClpP revealed a novel binding mode: Because of the rotation of the conserved residue proline 125, ClpP is locked in a defined conformational state, which results in distortion of the catalytic triad and inhibition of the peptidase activity. Based on these structural insights, the molecule was optimized by rational design and virtual screening, resulting in derivatives exceeding the potency of previous ClpP inhibitors. Strikingly, the conformational lock is overturned by binding of ClpX, an associated chaperone that enables proteolysis by substrate unfolding in the ClpXP complex. Thus, regulation of inhibitor binding by associated chaperones is an unexpected mechanism important for ClpP drug development., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)