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Identification of novel small-molecular inhibitors of Staphylococcus aureus sortase A using hybrid virtual screening.
Volynets, Galyna P; Barthels, Fabian; Hammerschmidt, Stefan J; Moshynets, Olena V; Lukashov, Sergiy S; Starosyla, Sergiy A; Vyshniakova, Hanna V; Iungin, Olga S; Bdzhola, Volodymyr G; Prykhod'ko, Andrii O; Syniugin, Anatolii R; Sapelkin, Vladislav M; Yarmoluk, Sergiy M; Schirmeister, Tanja.
  • Volynets GP; Department of Medicinal Chemistry, Institute of Molecular Biology and Genetics, the NAS of Ukraine, 150 Zabolotnogo St, 03143, Kyiv, Ukraine. g.p.volynets@gmail.com.
  • Barthels F; Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg-University of Mainz, Staudinger Weg 5, 55128, Mainz, Germany.
  • Hammerschmidt SJ; Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg-University of Mainz, Staudinger Weg 5, 55128, Mainz, Germany.
  • Moshynets OV; Biofilm study group, Institute of Molecular Biology and Genetics, the NAS of Ukraine, 150 Zabolotnogo St, 03143, Kyiv, Ukraine.
  • Lukashov SS; Department of Medicinal Chemistry, Institute of Molecular Biology and Genetics, the NAS of Ukraine, 150 Zabolotnogo St, 03143, Kyiv, Ukraine.
  • Starosyla SA; Department of Medicinal Chemistry, Institute of Molecular Biology and Genetics, the NAS of Ukraine, 150 Zabolotnogo St, 03143, Kyiv, Ukraine.
  • Vyshniakova HV; RECEPTOR.AI, Boston, MA, USA.
  • Iungin OS; L.V. Gromashevsky Institute of Epidemiology and Infectious Diseases NAMS of Ukraine, 5 Amosova St, 03038, Kyiv, Ukraine.
  • Bdzhola VG; Department of Functional Genomics, Institute of Molecular Biology and Genetics, the NAS of Ukraine, 150 Zabolotnogo St, 03143, Kyiv, Ukraine.
  • Prykhod'ko AO; Department of Medicinal Chemistry, Institute of Molecular Biology and Genetics, the NAS of Ukraine, 150 Zabolotnogo St, 03143, Kyiv, Ukraine.
  • Syniugin AR; Department of Medicinal Chemistry, Institute of Molecular Biology and Genetics, the NAS of Ukraine, 150 Zabolotnogo St, 03143, Kyiv, Ukraine.
  • Sapelkin VM; Research and Development Department, Scientific Services Company Otava Ltd, 150 Zabolotnogo St, 03143, Kyiv, Ukraine.
  • Yarmoluk SM; Department of Medicinal Chemistry, Institute of Molecular Biology and Genetics, the NAS of Ukraine, 150 Zabolotnogo St, 03143, Kyiv, Ukraine.
  • Schirmeister T; Department of Medicinal Chemistry, Institute of Molecular Biology and Genetics, the NAS of Ukraine, 150 Zabolotnogo St, 03143, Kyiv, Ukraine.
J Antibiot (Tokyo) ; 75(6): 321-332, 2022 06.
Article in English | MEDLINE | ID: covidwho-1878523
ABSTRACT
Staphylococcus aureus is one of the most dangerous pathogens commonly associated with high levels of morbidity and mortality. Sortase A is considered as a promising molecular target for the development of antistaphylococcal agents. Using hybrid virtual screening approach and FRET analysis, we have identified five compounds able to decrease the activity of sortase A by more than 50% at the concentration of 200 µM. The most promising compound was 2-(2-amino-3-chloro-benzoylamino)-benzoic acid which was able to inhibit S. aureus sortase A at the IC50 value of 59.7 µM. This compound was selective toward sortase A compared to other four cysteine proteases - cathepsin L, cathepsin B, rhodesain, and the SARS-CoV2 main protease. Microscale thermophoresis experiments confirmed that this compound bound sortase A with KD value of 189 µM. Antibacterial and antibiofilm assays also confirmed high specificity of the hit compound against two standard and three wild-type, S. aureus hospital infection isolates. The effect of the compound on biofilms produced by two S. aureus ATCC strains was also observed suggesting that the compound reduced biofilm formation by changing the biofilm structure and thickness.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Staphylococcal Infections / COVID-19 Type of study: Diagnostic study / Screening study Limits: Humans Language: English Journal: J Antibiot (Tokyo) Year: 2022 Document Type: Article Affiliation country: S41429-022-00524-8

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Staphylococcal Infections / COVID-19 Type of study: Diagnostic study / Screening study Limits: Humans Language: English Journal: J Antibiot (Tokyo) Year: 2022 Document Type: Article Affiliation country: S41429-022-00524-8