Discovery and development of substituted thiadiazoles as inhibitors of Staphylococcus aureus Sortase A. Issue 19 (1st October 2019)

• Record Type: Journal Article
• Authors: Wehrli, Patrick M.; Uzelac, Ivana; Olsson, Thomas; Jacso, Tomas; Tietze, Daniel; Gottfries, Johan
• Is Part Of: Bioorganic & medicinal chemistry. Volume 27:Issue 19(2019)
• Publication Date: 2019-10-01
• Subjects: Abz 2-aminobenzoyl -- BINAP 2, 2′-bis(diphenylphosphino)-1, 1′-binaphthyl -- CCUG Culture Collection University of Gothenburg -- CFU colony forming units -- CPMG Carr-Purcell-Meiboom-Gill -- DMSO dimethyl sulfoxide -- DBA direct binding assay -- dba dibenzylideneacetone -- 2 4-dinitrophenyl -- EDTA ethylenediamine-N, N, N', N'-tetraacetic acid -- ESI electrospray ionization -- FRET fluorescence resonance energy transfer -- HEPES 4-(2-Hydroxyethyl)piperazine-1-ethanesulfonic acid -- HMBC heteronuclear multiple bond correlation -- HMQC multiple-quantum coherence -- HTS high-throughput screening -- IC50 the half maximal inhibitory concentration -- LCBU Laboratories for Chemical Biology Umeå -- LCMS liquid chromatography mass spectrometry -- HRMS high mass resolution mass spectrometry -- MHB Mueller-Hinton broth -- MIC minimum inhibitory concentration -- MRSA methicillin-resistant Staphylococcus aureus -- NMR nuclear magnetic resonance -- PAINS pan-assay interference compounds -- SAR structure-activity relationship -- SrtA Sortase A enzyme -- srtA gene coding for SrtA -- TCEP Tris(2-carboxyethyl)phosphin -- THF tetrahydrofuran -- TLC thin layer chromatography -- Tris tris(hydroxymethyl)amino-methane -- p-TSA p-toluenesulfonic acid; Staphylococcus aureus -- Sortase A -- SrtA inhibitors -- Anti-virulence drugs -- Antimicrobial resistance; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2019.115043
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: High-throughput screening of small-molecule libraries has led to the identification of thiadiazoles as a new class of inhibitors against Staphylococcus aureus sortase A (SrtA). N-(5-((4-nitrobenzyl)thio)-1, 3, 4-thiadiazol-2-yl)nicotinamide (IC50 = 3.8 µM) was identified as a potent inhibitor of SrtA after synthetic modification of hit compounds. Additional ligands developed in this study displayed affinities in the low micromolar range without affecting bacterial growth in vitro . The study also suggest a new mode of action through covalent binding to the active site cysteine.