α-Methylene-γ-butyrolactones attenuate Staphylococcus aureus virulence by inhibition of transcriptional regulation

Covalent Modifiers: A Chemical Perspective on the Reactivity of α,β-Unsaturated Carbonyls with Thiols via Hetero-Michael Addition Reactions

“…This compound-centric approach by Sieber and co-workers showed that these compounds reacted with many proteins within bacterial proteomes, 88b which is consistent with related studies in human cells. A select number of proteins were identified with LC-MS/MS and proteomic analysis, including katG, ahpC, and thil; another study found that 220 and 221 labeled TrxA, staphylococcal disulfide reductase, and three transcriptional regulators in bacteria (SarA, SarR, and MgrA).…”

“…90 A subsequent report identified additional proteins involved in management of AML oxidative stress as direct targets. 88c These data as well as unpublished work from one of our laboratories support that many SLs containing α-methylene-γ-lactones are targeting multiple proteins with a cell proteome bearing accessible cysteines.…”

“…Attachment of reporter tags (e.g., biotinylation, ‘clickable’ reporters such as alkynes and azides) to natural products or synthetic derivatives containing α-methylene-γ-lactones has allowed for identification of their covalent protein targets. 88 Within live cell culture and in cell lysate it has been determined that, under physiological conditions, probes containing α-methylene-γ-lactones irreversibly target thiols and withstand conditions used for protein pulldown studies (see Figure 26). However, detailed kinetic studies of the reactivities of α-methylene-γ-lactones and their thiol targets (e.g., thiol side chains on proteins; cysteine, GSH) are limited.…”

Staphylococcus aureus Aggregation and Coagulation Mechanisms, and Their Function in Host–Pathogen Interactions

“…One MgrA inhibitor, 5,5-methylenedisalicylic acid, has been shown to prevent formation of organ abscesses during S. aureus sepsis (Sun et al, 2011). Some of the α-methylene-γ-butyrolactones inhibit both MgrA and other staphylococcal transcriptional regulators like SarA and SarR, thus exhibiting potentially powerful, combined antivirulent action (Kunzmann et al, 2014). Extracts of Sargassum pallidium seaweed and Cinnamomum cassia tree were also shown to interfere with MgrA, yet the exact active compounds were not identified(Wang et al, 2015).…”

Thermo-triggered release of a Cys probe from the cavity of a water-soluble pillar[5]arene

“…Therefore, it is still a big challenge to develop thiol-specific probe systems with biocompatibility to detect thiols in specific regions as we expected. 3 Pillar[n]arenes, 4,5 a new generation of macrocyclic hosts next to crown ethers, 6 cyclodextrins, 7 calixarenes, 8 and cucurbiturils, 9 have been developed rapidly because of their unique structures and high functionality, bringing along many applications in the fabrication of interesting and functional supramolecular systems, such as supramolecular polymers, drug delivery systems, transmembrane channels, thermo-responsive materials, and hybrid porous materials. 10 Especially, neutral water-soluble pillar[n]arenes bearing triethylene oxide chains have been demonstrated to be excellent hosts for molecules of various sizes and shapes in water.…”