Development of novel membrane disrupting lipoguanidine compounds sensitizing Gram-negative bacteria to antibiotics

Seong Heun Kim, Charlotte K. Hind, Guilherme Felipe Dos Santos Fernandes, Jingyue Wu, Manare Molahlegi Dorothy Semenya, Melanie Clifford, Caleb Marsh, Silvia Anselmi, James Mason, Kenneth Bruce, John Sutton, Daniele Castagnolo*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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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 languageEnglish
Pages (from-to)239-249
Number of pages11
JournalAcs Medicinal Chemistry Letters
Volume15
Issue number2
DOIs
Publication statusPublished - 8 Feb 2024

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