In-Silico Identified New Natural Sortase A Inhibitors Disrupt S. aureus Biofilm Formation

Singapore Institute of Food and Biotechnology Innovation (SIFBI), Agency for Science, Technology and Research (A*STAR), 31 Biopolis Way, #01-02 Nanos, Singapore 138669, Singapore

Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), 30 Biopolis Street, #07-01 Matrix, Singapore 138671, Singapore

Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, #3-09 Proteos, Singapore 138673, Singapore

Authors to whom correspondence should be addressed.

^†

These two authors contributed equally to this work.

Int. J. Mol. Sci. 2020, 21(22), 8601; https://doi.org/10.3390/ijms21228601

Received: 11 October 2020 / Revised: 9 November 2020 / Accepted: 12 November 2020 / Published: 14 November 2020

(This article belongs to the Section Molecular Microbiology)

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Abstract

Sortase A (SrtA) is a membrane-associated enzyme that anchors surface-exposed proteins to the cell wall envelope of Gram-positive bacteria such as Staphylococcus aureus. As SrtA is essential for Gram-positive bacterial pathogenesis but dispensable for microbial growth or viability, SrtA is considered a favorable target for the enhancement of novel anti-infective drugs that aim to interfere with key bacterial virulence mechanisms, such as biofilm formation, without developing drug resistance. Here, we used virtual screening to search an in-house natural compound library and identified two natural compounds, N1287 (Skyrin) and N2576 ((4,5-dichloro-1H-pyrrol-2-yl)-[2,4-dihydroxy-3-(4-methyl-pentyl)-phenyl]-methanone) that inhibited the enzymatic activity of SrtA. These compounds also significantly reduced the growth of S. aureus but possessed moderate mammalian toxicity. Furthermore, S. aureus strains treated with these compounds exhibited reduction in adherence to host fibrinogen, as well as biofilm formation. Hence, these compounds may represent an anti-infective therapy without the side effects of antibiotics. View Full-Text

Keywords: anti-biofilm activity; sortase A inhibitor; Staphylococcus aureus; MRSA; fibrinogen; molecular docking; virtual screening; natural products; skyrin

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Thappeta, K.R.V.; Zhao, L.N.; Nge, C.E.; Crasta, S.; Leong, C.Y.; Ng, V.; Kanagasundaram, Y.; Fan, H.; Ng, S.B. In-Silico Identified New Natural Sortase A Inhibitors Disrupt S. aureus Biofilm Formation. Int. J. Mol. Sci. 2020, 21, 8601. https://doi.org/10.3390/ijms21228601

AMA Style

Thappeta KRV, Zhao LN, Nge CE, Crasta S, Leong CY, Ng V, Kanagasundaram Y, Fan H, Ng SB. In-Silico Identified New Natural Sortase A Inhibitors Disrupt S. aureus Biofilm Formation. International Journal of Molecular Sciences. 2020; 21(22):8601. https://doi.org/10.3390/ijms21228601

Chicago/Turabian Style

Thappeta, Kishore R.V., Li N. Zhao, Choy E. Nge, Sharon Crasta, Chung Y. Leong, Veronica Ng, Yoganathan Kanagasundaram, Hao Fan, and Siew B. Ng. 2020. "In-Silico Identified New Natural Sortase A Inhibitors Disrupt S. aureus Biofilm Formation" International Journal of Molecular Sciences 21, no. 22: 8601. https://doi.org/10.3390/ijms21228601

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In-Silico Identified New Natural Sortase A Inhibitors Disrupt S. aureus Biofilm Formation

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