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

Lee, Kyu Myung; Le, Philipp; Sieber, Stephan A.; Hacker, Stephan M.

doi:10.1039/c9cc09204h

Cited by 20 publications

(14 citation statements)

References 24 publications

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“…44 The latter include catalytic nucleophiles (Cys-151 in gapA1, Cys-2 in glmS and Cys-102 of mnmA), other active site residues (Cys-134 in trxB and Cys-112 in fabH), residues of metal binding sites (Cys-24 of rpsZ, Cys-100 of glmU, Cys-829 in secA1 and Cys-38 in tarJ) and residues of nucleotide binding sites (Cys-44 and Cys-275 in metK). 44 In line with what we observed for organic molecules as competitors, 45 we detected concentrationdependent competition for many cysteines (Fig. 2d) that could be fit with a dose response model, indicating that the isoDTB-ABPP method gives quantitative, residuespecific engagement data also for organometallic compounds.…”

Section: Introductionsupporting

confidence: 83%

Competitive Profiling of Ligandable Cysteines in Staphylococcus aureus with an Organogold Compound

Schmidt

Zollo

Bonsignore

et al. 2022

Preprint

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With the idea of exploiting metal-templated reactions to achieve selective modification of cysteines in proteins for antibacterial applications, an organometallic cyclometalated Au(III) compound was explored in a competitive chemoproteomic approach based on the isoDTB-ABPP (isotopically labelled desthiobiotin azide-activity-based protein profiling) technology in S. aureus cell extracts. In this way, more than 100 ligandable cysteines where identified, of which 10 were close to functional sites of proteins encoded by essential genes indicating potential for antibiotic development. Interestingly, more than 50% of the identified ligandable sites were not engaged by organic α-chloroacetamides in a previous study, indicating that organometallic compounds expand the ligandable space in bacteria. A selected interaction identified by isoDTB-ABPP was validated using an enzyme activity assay, and intact protein mass spectrometry showed that cysteine arylation of an unprecedented target occurs with the studied compound. The obtained results constitute the proof-of-concept that this family of organogold compounds has potential for therapeutic protein targeting via selective, covalent modification of cysteine residues in bacteria. Looking more broadly, our study demonstrates that the targets of cyclometalated gold compounds can be studied proteome-wide with competitive residue-specific chemoproteomics enabling the expansion of the known ligandable proteome to sites that can be addressed with this compound class.

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Section: Introductionsupporting

confidence: 83%

Competitive Profiling of Ligandable Cysteines in Staphylococcus aureus with an Organogold Compound

Schmidt

Zollo

Bonsignore

et al. 2022

Preprint

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“…This will be especially important for ligands, for which probe synthesis is challenging or which form covalent adducts that evade direct detection like those forming unstable modifications such as thioesters 13 or covalently reversible protein adducts. 14,15 It is tempting to speculate that in the future it will be possible to use a mixture of several probes to competitively profile the selectivity of a protein ligand simultaneously at various amino acids within the same proteomic experiment as has recently been described for the combined detection of cysteines and lysines. 13 Taking all of this together, we report on an unbiased, universal workflow to characterise amino acid selectivity of electrophilic compounds in the whole proteome.…”

Section: Discussionmentioning

confidence: 99%

Profiling the proteome-wide selectivity of diverse electrophiles

Zanon

Zhang

et al. 2021

Preprint

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Targeted covalent inhibitors are powerful entities in drug discovery, but their application has so far mainly been limited to addressing cysteine residues. The development of cysteine-directed covalent inhibitors has largely profited from determining their proteome-wide selectivity using competitive residue-specific proteomics. Several probes have recently been described to monitor other amino acids using this technology and many more electrophiles exist to modify proteins. Nevertheless, a direct, proteome-wide comparison of the selectivity of diverse probes is still entirely missing. Here, we developed a completely unbiased workflow to analyse electrophile selectivity proteome-wide and applied it to directly compare 54 alkyne probes containing diverse reactive groups. In this way, we verified and newly identified probes to monitor a total of nine different amino acids as well as the N-terminus proteome-wide. This selection includes the first probes to globally monitor tryptophans, histidines and arginines as well as novel tailored probes for methionines, aspartates and glutamates.

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Section: Resultsmentioning

confidence: 99%

“…for acylating reagents that form unstable thioesters at cysteine, which evade direct detection. 13 Similarly, this approach is not suitable for reversibly covalent inhibitors, 14,15 whose modifications would also be lost before the analysis. In contrast, if one broadly reactive alkyne probe is developed that leads to a stable modification of an amino acid of interest, the targets for all of these compounds can be identified competitively.…”

Section: Introductionmentioning

confidence: 99%

Profiling the Proteome-Wide Selectivity of Diverse Electrophiles

Zanon¹,

Yu²,

Zhang³

et al. 2021

Preprint

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<a>Targeted covalent inhibitors are powerful entities in drug discovery, but their application has so far mainly been limited to addressing cysteine residues. The development of cysteine-directed covalent inhibitors has largely profited from determining their proteome-wide selectivity using competitive residue-specific proteomics. Several probes have recently been described to monitor other amino acids using this technology and many more electrophiles exist to modify proteins. Nevertheless, a direct, proteome‑wide comparison of the selectivity of diverse probes is still entirely missing. Here, we developed a completely unbiased workflow to analyse electrophile selectivity proteome‑wide and applied it to directly compare 54 alkyne probes containing diverse reactive groups. In this way, we verified and newly identified probes to monitor a total of nine different amino acids as well as the N‑terminus proteome‑wide. This selection includes the first probes to globally monitor tryptophans, histidines and arginines as well as novel tailored probes for methionines, aspartates and glutamates.</a>

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

Abstract: Degrasyn was found to exhibit antibiotic activity against multi-resistant Staphylococcus aureus. Chemical proteomics revealed insights into its mode of action.

Cited by 20 publications

References 24 publications

Competitive Profiling of Ligandable Cysteines in Staphylococcus aureus with an Organogold Compound

Competitive Profiling of Ligandable Cysteines in Staphylococcus aureus with an Organogold Compound

Profiling the proteome-wide selectivity of diverse electrophiles

Profiling the Proteome-Wide Selectivity of Diverse Electrophiles

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