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Identification of novel small-molecular inhibitors of Staphylococcus aureus sortase A using hybrid virtual screening

The Journal of Antibiotics volume 75, pages 321–332 (2022)Cite this article

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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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Author information

Authors and Affiliations

  1. Department of Medicinal Chemistry, Institute of Molecular Biology and Genetics, the NAS of Ukraine, 150 Zabolotnogo St, 03143, Kyiv, Ukraine

    Galyna P. Volynets, Sergiy S. Lukashov, Sergiy A. Starosyla, Volodymyr G. Bdzhola, Andrii O. Prykhod’ko, Anatolii R. Syniugin, Vladislav M. Sapelkin & Sergiy M. Yarmoluk

  2. Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg-University of Mainz, Staudinger Weg 5, 55128, Mainz, Germany

    Fabian Barthels, Stefan J. Hammerschmidt & Tanja Schirmeister

  3. Biofilm study group, Institute of Molecular Biology and Genetics, the NAS of Ukraine, 150 Zabolotnogo St, 03143, Kyiv, Ukraine

    Olena V. Moshynets

  4. RECEPTOR.AI, Boston, MA, USA

    Sergiy A. Starosyla

  5. L.V. Gromashevsky Institute of Epidemiology and Infectious Diseases NAMS of Ukraine, 5 Amosova St, 03038, Kyiv, Ukraine

    Hanna V. Vyshniakova

  6. Department of Functional Genomics, Institute of Molecular Biology and Genetics, the NAS of Ukraine, 150 Zabolotnogo St, 03143, Kyiv, Ukraine

    Olga S. Iungin

  7. Research and Development Department, Scientific Services Company Otava Ltd, 150 Zabolotnogo St, 03143, Kyiv, Ukraine

    Andrii O. Prykhod’ko

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  1. Galyna P. Volynets
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Correspondence to Galyna P. Volynets.

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Volynets, G.P., Barthels, F., Hammerschmidt, S.J. et al. Identification of novel small-molecular inhibitors of Staphylococcus aureus sortase A using hybrid virtual screening. J Antibiot 75, 321–332 (2022). https://doi.org/10.1038/s41429-022-00524-8

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