An Aromatic Hydroxyamide Attenuates Multiresistant Staphylococcus aureus Toxin Expression

Abstract

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.

Degrasyn exhibits antibiotic activity against multi-resistantStaphylococcus aureusby modifying several essential cysteines

“…1B). 5,11 Satisfyingly, the antibiotic activity was retained in all MRSA strains (MIC r 12.5 mM) suggesting a different mode-of-action as compared to existing drugs.…”

“…-OH, -OMe, etc.) were largely not tolerated (11,12,13), the introduction of a difluoroacetal moiety (14) retained full activity. Satisfyingly, substitution with an alkyne handle (15) only slightly increased the MIC, which is a prerequisite for subsequent target identification using conventional ABPP.…”

Targeting the endoplasmic reticulum-mitochondria interface sensitizes leukemia cells to cytostatics

“…(B) Principle of activity-based protein profiling with the PS89 photo probe covalently linked to its cellular targets (adapted from Vomacka et al . 30 ). (C) Volcano plot of target proteins enriched by the PS89 photo probe versus dimethyl sulfoxide (DMSO) (left).…”

“…Sample preparation and mass spectrometry analysis of target proteins by gel-free activity-based protein profiling and dimethyl labeling was performed as previously described. 30 Cutoff criteria for target identification were: (i) enrichment by photo probe log 2 Probe/DMSO >1.6, -log 10 P -value >2 and (ii) PS89 competition log 2 Probe/PS89 >0. The data shown are the results of three biological replicates.…”

Dual Inhibitor of Staphylococcus aureus Virulence and Biofilm Attenuates Expression of Major Toxins and Adhesins

“…21,22 In our search for optimized antivirulence compounds, we recently identified hydroxyamide fatty acids as potent and durable inhibitors of hla expression. 23 The most potent hydroxyamide compound AV59 was effective in an abscess mouse model and did not reveal any in vitro resistance development. A mode of action analysis by affinity-based protein profiling (AfBPP) with an alkyne tagged photo-crosslinker derivative of AV59 unraveled several target proteins including MntC, an essential component of manganese transport and confirmed antivirulence target.…”