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Covalent inhibitors of bacterial peptidoglycan biosynthesis enzyme MurA with chloroacetamide warheadGrabrijan, Katarina ...MurA (UDP-N-acetylglucosamine enolpyruvyl transferase) catalyzes the first committed step in the cytoplasmic part of peptidoglycan biosynthesis and is a validated target enzyme for antibacterial drug ... discovery; the inhibitor fosfomycin has been used clinically for decades. Like fosfomycin, most MurA inhibitors are small heterocyclic compounds that inhibit the enzyme by forming a covalent bond with the active site cysteine. The reactive chloroacetamide group was selected from a series of suitable electrophilic thiol-reactive warheads. The predominantly one-step synthesis led to the construction of the final library of 47 fragment-sized chloroacetamide compounds. Several new E. coli MurA inhibitors were identified, with the most potent compound having an IC50 value in the low micromolar range. The electrophilic reactivity of all chloroacetamide fragments in our library was evaluated by a high-throughput spectrophotometric assay using the reduced Ellman reagent as a surrogate for the cysteine thiol. LC-MS/MS experiments confirmed the covalent binding of the most potent inhibitor to Cys115 of the digested MurA enzyme. The covalent binding was further investigated by a biochemical time-dependent assay and a dilution assay, which confirmed the irreversible and time-dependent mode of action. The efficacy of chloroacetamide derivatives against MurA does not correlate with their thiol reactivity, making the active fragments valuable starting points for fragment-based development of new antibacterial agents targeting MurA.Source: European journal of medicinal chemistry. - ISSN 0223-5234 (Vol. 243, 2022, 15 str.)Type of material - article, component part ; adult, seriousPublish date - 2022Language - englishCOBISS.SI-ID - 123442179
Author
Grabrijan, Katarina |
Hrast, Martina |
Proj, Matic |
Dolšak, Ana, farmacevtka, 1993- |
Zdovc, Irena |
Imre, Tímea |
Petri, László |
Ábrányi-Balogh, Péter |
Keserü M., György |
Gobec, Stanislav, 1970-
Topics
Bakterije |
Farmacevtska kemija |
antibakterijska sredstva |
UDP-N-acetilglukozamin enolpiruvil transferaza |
tiolna reaktivnost |
antibacterial agents |
UDP-N-Acetylglucosamine enolpyruvyl transferase |
thiol reactivity
Author | Grabrijan, Katarina ... |
Title | Covalent inhibitors of bacterial peptidoglycan biosynthesis enzyme MurA with chloroacetamide warhead |
Publication date | 2022-12-29 |
COBISS.SI-ID | 123442179 |
Publication version in repository | Publisher's version |
Publication licence | Creative Commons Attribution 4.0 International |
Embargo | Immediate publication for public |
Project(s) from which the publication was funded
Title | Acronym | Project ID | Funder |
---|---|---|---|
Farmacevtska kemija: načrtovanje, sinteza in vrednotenje učinkovin | P1-0208-2022 |
Javna agencija za znanstvenoraziskovalno in inovacijsko dejavnost Republike Slovenije |
|
Kovalentni pristop k boju proti bakterijski rezistenci | N1-0169-2021 |
Javna agencija za znanstvenoraziskovalno in inovacijsko dejavnost Republike Slovenije |
|
Razvoj protibakteriskih učinkovin z delovanjem na validirane tarče v biosintezi peptidoglikana | J1-2484-2020 |
Javna agencija za znanstvenoraziskovalno in inovacijsko dejavnost Republike Slovenije |
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https://www.sciencedirect.com/science/article/pii/S0223523422006547?via%3Dihub#! |
https://repozitorij.uni-lj.si/IzpisGradiva.php?id=141439 |
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Database name | Field | Year |
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Links to authors' personal bibliographies | Links to information on researchers in the SICRIS system |
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Grabrijan, Katarina | 50814 |
Hrast, Martina | 32036 |
Proj, Matic | 52376 |
Dolšak, Ana, farmacevtka, 1993- | 50400 |
Zdovc, Irena | 12682 |
Imre, Tímea | |
Petri, László | |
Ábrányi-Balogh, Péter | |
Keserü M., György | |
Gobec, Stanislav, 1970- | 15284 |
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