Development of Novel Membrane Disrupting Lipoguanidine Compounds Sensitizing Gram-Negative Bacteria to Antibiotics

Seong Heun Kim; Charlotte K. Hind; Guilherme F.S. Fernandes; Jingyue Wu; Dorothy Semenya; Melanie Clifford; Caleb Marsh; Silvia Anselmi; A. James Mason; Kenneth D. Bruce; J. Mark Sutton; Daniele Castagnolo

doi:10.1021/acsmedchemlett.3c00460

Development of Novel Membrane Disrupting Lipoguanidine Compounds Sensitizing Gram-Negative Bacteria to Antibiotics

Seong Heun Kim, Charlotte K. Hind, Guilherme F.S. Fernandes, Jingyue Wu, Dorothy Semenya, Melanie Clifford, Caleb Marsh, Silvia Anselmi, A. James Mason, Kenneth D. Bruce, J. Mark Sutton^*, Daniele Castagnolo^*

^*Corresponding author for this work

Research & Technical Staff

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

Abstract

A new class of amphiphilic molecules, the lipoguanidines, designed as hybrids of guanidine and fatty acid compounds, has been synthesized and developed. The new molecules present both a guanidine polar head and a lipophilic tail that allow them to disrupt bacterial membranes and to sensitize Gram-negative bacteria to the action of the narrow-spectrum antibiotics rifampicin and novobiocin. The lipoguanidine 5g sensitizes Klebsiella pneumonia, Acinetobacter baumannii, Pseudomonas aeruginosa, and Escherichia coli to rifampicin, thereby reducing the antibiotic minimum inhibitory concentrations (MIC) up to 256-fold. Similarly, 5g is able to potentiate novobiocin up to 64-fold, thereby showing a broad spectrum of antibiotic potentiating activity. Toxicity and mechanism studies revealed the potential of 5g to work synergistically with rifampicin through the disruption of bacterial membranes without affecting eukaryotic cells.

Original language	English
Pages (from-to)	239-249
Number of pages	11
Journal	ACS Medicinal Chemistry Letters
Volume	15
Issue number	2
DOIs	https://doi.org/10.1021/acsmedchemlett.3c00460
Publication status	Published - 8 Feb 2024

Bibliographical note

Publisher Copyright:
© 2024 The Authors. Published by American Chemical Society

Keywords

Antibacterials
Antibiotic
Guanidine
Lipoguanidine
Synergistic Activity

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Kim, S. H., Hind, C. K., Fernandes, G. F. S., Wu, J., Semenya, D., Clifford, M., Marsh, C., Anselmi, S., Mason, A. J., Bruce, K. D., Sutton, J. M., & Castagnolo, D. (2024). Development of Novel Membrane Disrupting Lipoguanidine Compounds Sensitizing Gram-Negative Bacteria to Antibiotics. ACS Medicinal Chemistry Letters, 15(2), 239-249. https://doi.org/10.1021/acsmedchemlett.3c00460

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title = "Development of Novel Membrane Disrupting Lipoguanidine Compounds Sensitizing Gram-Negative Bacteria to Antibiotics",

abstract = "A new class of amphiphilic molecules, the lipoguanidines, designed as hybrids of guanidine and fatty acid compounds, has been synthesized and developed. The new molecules present both a guanidine polar head and a lipophilic tail that allow them to disrupt bacterial membranes and to sensitize Gram-negative bacteria to the action of the narrow-spectrum antibiotics rifampicin and novobiocin. The lipoguanidine 5g sensitizes Klebsiella pneumonia, Acinetobacter baumannii, Pseudomonas aeruginosa, and Escherichia coli to rifampicin, thereby reducing the antibiotic minimum inhibitory concentrations (MIC) up to 256-fold. Similarly, 5g is able to potentiate novobiocin up to 64-fold, thereby showing a broad spectrum of antibiotic potentiating activity. Toxicity and mechanism studies revealed the potential of 5g to work synergistically with rifampicin through the disruption of bacterial membranes without affecting eukaryotic cells.",

keywords = "Antibacterials, Antibiotic, Guanidine, Lipoguanidine, Synergistic Activity",

author = "Kim, {Seong Heun} and Hind, {Charlotte K.} and Fernandes, {Guilherme F.S.} and Jingyue Wu and Dorothy Semenya and Melanie Clifford and Caleb Marsh and Silvia Anselmi and Mason, {A. James} and Bruce, {Kenneth D.} and Sutton, {J. Mark} and Daniele Castagnolo",

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doi = "10.1021/acsmedchemlett.3c00460",

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Kim, SH, Hind, CK, Fernandes, GFS, Wu, J, Semenya, D, Clifford, M, Marsh, C, Anselmi, S, Mason, AJ, Bruce, KD, Sutton, JM & Castagnolo, D 2024, 'Development of Novel Membrane Disrupting Lipoguanidine Compounds Sensitizing Gram-Negative Bacteria to Antibiotics', ACS Medicinal Chemistry Letters, vol. 15, no. 2, pp. 239-249. https://doi.org/10.1021/acsmedchemlett.3c00460

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AU - Kim, Seong Heun

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AU - Fernandes, Guilherme F.S.

AU - Wu, Jingyue

AU - Semenya, Dorothy

AU - Clifford, Melanie

AU - Marsh, Caleb

AU - Anselmi, Silvia

AU - Mason, A. James

AU - Bruce, Kenneth D.

AU - Sutton, J. Mark

AU - Castagnolo, Daniele

PY - 2024/2/8

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N2 - A new class of amphiphilic molecules, the lipoguanidines, designed as hybrids of guanidine and fatty acid compounds, has been synthesized and developed. The new molecules present both a guanidine polar head and a lipophilic tail that allow them to disrupt bacterial membranes and to sensitize Gram-negative bacteria to the action of the narrow-spectrum antibiotics rifampicin and novobiocin. The lipoguanidine 5g sensitizes Klebsiella pneumonia, Acinetobacter baumannii, Pseudomonas aeruginosa, and Escherichia coli to rifampicin, thereby reducing the antibiotic minimum inhibitory concentrations (MIC) up to 256-fold. Similarly, 5g is able to potentiate novobiocin up to 64-fold, thereby showing a broad spectrum of antibiotic potentiating activity. Toxicity and mechanism studies revealed the potential of 5g to work synergistically with rifampicin through the disruption of bacterial membranes without affecting eukaryotic cells.

AB - A new class of amphiphilic molecules, the lipoguanidines, designed as hybrids of guanidine and fatty acid compounds, has been synthesized and developed. The new molecules present both a guanidine polar head and a lipophilic tail that allow them to disrupt bacterial membranes and to sensitize Gram-negative bacteria to the action of the narrow-spectrum antibiotics rifampicin and novobiocin. The lipoguanidine 5g sensitizes Klebsiella pneumonia, Acinetobacter baumannii, Pseudomonas aeruginosa, and Escherichia coli to rifampicin, thereby reducing the antibiotic minimum inhibitory concentrations (MIC) up to 256-fold. Similarly, 5g is able to potentiate novobiocin up to 64-fold, thereby showing a broad spectrum of antibiotic potentiating activity. Toxicity and mechanism studies revealed the potential of 5g to work synergistically with rifampicin through the disruption of bacterial membranes without affecting eukaryotic cells.

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JF - ACS Medicinal Chemistry Letters

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Development of Novel Membrane Disrupting Lipoguanidine Compounds Sensitizing Gram-Negative Bacteria to Antibiotics

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Keywords

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