Sialic Acid Derivatives Inhibit SiaT Transporters and Delay Bacterial Growth

Tiago Bozzola; Mariafrancesca Scalise; Christer U. Larsson; Michael C. Newton-Vesty; Caterina Rovegno; Ankita Mitra; Jonathan Cramer; Weixiao Yuan Wahlgren; Partha Radhakrishnan Santhakumari; Richard E. Johnsson; Oliver Schwardt; Beat Ernst; Rosmarie Friemann; Renwick C.J. Dobson; Cesare Indiveri; Jenny Schelin; Ulf J. Nilsson; Ulf Ellervik

doi:10.1021/acschembio.2c00321

Sialic Acid Derivatives Inhibit SiaT Transporters and Delay Bacterial Growth

Tiago Bozzola, Mariafrancesca Scalise, Christer U. Larsson, Michael C. Newton-Vesty, Caterina Rovegno, Ankita Mitra, Jonathan Cramer, Weixiao Yuan Wahlgren, Partha Radhakrishnan Santhakumari, Richard E. Johnsson, Oliver Schwardt, Beat Ernst, Rosmarie Friemann, Renwick C.J. Dobson, Cesare Indiveri, Jenny Schelin, Ulf J. Nilsson, Ulf Ellervik

Research output: Contribution to journal › Article › peer-review

Abstract

Antibiotic resistance is a major worldwide concern, and new drugs with mechanistically novel modes of action are urgently needed. Here, we report the structure-based drug design, synthesis, and evaluation in vitro and in cellular systems of sialic acid derivatives able to inhibit the bacterial sialic acid symporter SiaT. We designed and synthesized 21 sialic acid derivatives and screened their affinity for SiaT by a thermal shift assay and elucidated the inhibitory mechanism through binding thermodynamics, computational methods, and inhibitory kinetic studies. The most potent compounds, which have a 180-fold higher affinity compared to the natural substrate, were tested in bacterial growth assays and indicate bacterial growth delay in methicillin-resistant Staphylococcus aureus. This study represents the first example and a promising lead in developing sialic acid uptake inhibitors as novel antibacterial agents.

Original language	English
Pages (from-to)	1890-1900
Number of pages	11
Journal	ACS Chemical Biology
Volume	17
Issue number	7
DOIs	https://doi.org/10.1021/acschembio.2c00321
Publication status	Published - 2022 Jul 15

Subject classification (UKÄ)

Medicinal Chemistry

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10.1021/acschembio.2c00321Licence: CC BY

Siametics: Design and synthesis of sialic acid derivatives to block bacterial sialic acid uptake
Ellervik, U. (Researcher), Nilsson, U. (Researcher), Björklund, J. (Research student), Bozzola, T. (Research student), Schelin, J. (Researcher), Schwardt, O. (Researcher), Ramaswamy, S. (Researcher) & Indiveri, C. (Researcher)
Crafoord Foundation
2017/01/01 → …
Project: Research

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Bozzola, T., Scalise, M., Larsson, C. U., Newton-Vesty, M. C., Rovegno, C., Mitra, A., Cramer, J., Wahlgren, W. Y., Radhakrishnan Santhakumari, P., Johnsson, R. E., Schwardt, O., Ernst, B., Friemann, R., Dobson, R. C. J., Indiveri, C., Schelin, J., Nilsson, U. J., & Ellervik, U. (2022). Sialic Acid Derivatives Inhibit SiaT Transporters and Delay Bacterial Growth. ACS Chemical Biology, 17(7), 1890-1900. https://doi.org/10.1021/acschembio.2c00321

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title = "Sialic Acid Derivatives Inhibit SiaT Transporters and Delay Bacterial Growth",

abstract = "Antibiotic resistance is a major worldwide concern, and new drugs with mechanistically novel modes of action are urgently needed. Here, we report the structure-based drug design, synthesis, and evaluation in vitro and in cellular systems of sialic acid derivatives able to inhibit the bacterial sialic acid symporter SiaT. We designed and synthesized 21 sialic acid derivatives and screened their affinity for SiaT by a thermal shift assay and elucidated the inhibitory mechanism through binding thermodynamics, computational methods, and inhibitory kinetic studies. The most potent compounds, which have a 180-fold higher affinity compared to the natural substrate, were tested in bacterial growth assays and indicate bacterial growth delay in methicillin-resistant Staphylococcus aureus. This study represents the first example and a promising lead in developing sialic acid uptake inhibitors as novel antibacterial agents.",

author = "Tiago Bozzola and Mariafrancesca Scalise and Larsson, {Christer U.} and Newton-Vesty, {Michael C.} and Caterina Rovegno and Ankita Mitra and Jonathan Cramer and Wahlgren, {Weixiao Yuan} and {Radhakrishnan Santhakumari}, Partha and Johnsson, {Richard E.} and Oliver Schwardt and Beat Ernst and Rosmarie Friemann and Dobson, {Renwick C.J.} and Cesare Indiveri and Jenny Schelin and Nilsson, {Ulf J.} and Ulf Ellervik",

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month = jul,

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doi = "10.1021/acschembio.2c00321",

language = "English",

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Bozzola, T, Scalise, M, Larsson, CU, Newton-Vesty, MC, Rovegno, C, Mitra, A, Cramer, J, Wahlgren, WY, Radhakrishnan Santhakumari, P, Johnsson, RE, Schwardt, O, Ernst, B, Friemann, R, Dobson, RCJ, Indiveri, C, Schelin, J , Nilsson, UJ & Ellervik, U 2022, 'Sialic Acid Derivatives Inhibit SiaT Transporters and Delay Bacterial Growth', ACS Chemical Biology, vol. 17, no. 7, pp. 1890-1900. https://doi.org/10.1021/acschembio.2c00321

TY - JOUR

T1 - Sialic Acid Derivatives Inhibit SiaT Transporters and Delay Bacterial Growth

AU - Bozzola, Tiago

AU - Scalise, Mariafrancesca

AU - Larsson, Christer U.

AU - Newton-Vesty, Michael C.

AU - Rovegno, Caterina

AU - Mitra, Ankita

AU - Cramer, Jonathan

AU - Wahlgren, Weixiao Yuan

AU - Radhakrishnan Santhakumari, Partha

AU - Johnsson, Richard E.

AU - Schwardt, Oliver

AU - Ernst, Beat

AU - Friemann, Rosmarie

AU - Dobson, Renwick C.J.

AU - Indiveri, Cesare

AU - Schelin, Jenny

AU - Nilsson, Ulf J.

AU - Ellervik, Ulf

PY - 2022/7/15

Y1 - 2022/7/15

N2 - Antibiotic resistance is a major worldwide concern, and new drugs with mechanistically novel modes of action are urgently needed. Here, we report the structure-based drug design, synthesis, and evaluation in vitro and in cellular systems of sialic acid derivatives able to inhibit the bacterial sialic acid symporter SiaT. We designed and synthesized 21 sialic acid derivatives and screened their affinity for SiaT by a thermal shift assay and elucidated the inhibitory mechanism through binding thermodynamics, computational methods, and inhibitory kinetic studies. The most potent compounds, which have a 180-fold higher affinity compared to the natural substrate, were tested in bacterial growth assays and indicate bacterial growth delay in methicillin-resistant Staphylococcus aureus. This study represents the first example and a promising lead in developing sialic acid uptake inhibitors as novel antibacterial agents.

AB - Antibiotic resistance is a major worldwide concern, and new drugs with mechanistically novel modes of action are urgently needed. Here, we report the structure-based drug design, synthesis, and evaluation in vitro and in cellular systems of sialic acid derivatives able to inhibit the bacterial sialic acid symporter SiaT. We designed and synthesized 21 sialic acid derivatives and screened their affinity for SiaT by a thermal shift assay and elucidated the inhibitory mechanism through binding thermodynamics, computational methods, and inhibitory kinetic studies. The most potent compounds, which have a 180-fold higher affinity compared to the natural substrate, were tested in bacterial growth assays and indicate bacterial growth delay in methicillin-resistant Staphylococcus aureus. This study represents the first example and a promising lead in developing sialic acid uptake inhibitors as novel antibacterial agents.

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DO - 10.1021/acschembio.2c00321

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VL - 17

SP - 1890

EP - 1900

JO - ACS Chemical Biology

JF - ACS Chemical Biology

IS - 7

ER -

Sialic Acid Derivatives Inhibit SiaT Transporters and Delay Bacterial Growth

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Siametics: Design and synthesis of sialic acid derivatives to block bacterial sialic acid uptake

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