posted on 2024-01-09, 16:37authored bySeong-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
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.