TY - JOUR
T1 - Development of novel membrane disrupting lipoguanidine compounds sensitizing Gram-negative bacteria to antibiotics
AU - Kim, Seong Heun
AU - Hind, Charlotte K.
AU - Dos Santos Fernandes, Guilherme Felipe
AU - Wu, Jingyue
AU - Semenya, Manare Molahlegi Dorothy
AU - Clifford, Melanie
AU - Marsh, Caleb
AU - Anselmi, Silvia
AU - Mason, James
AU - Bruce, Kenneth
AU - Sutton, John
AU - Castagnolo, Daniele
N1 - Funding Information:
For G.F.S.F. and D.C. this project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 101027065. D.S. and D.C. acknowledge the South African National Research Foundation-SARChI for financial support to D.S. D.C. acknowledges BBSRC LIDo (BB/M009513/1) for Ph.D. Studentships to S.A. A.J.M. and D.C. acknowledge NC3Rs (NC/T001240/1) for financial support. D.C. and J.W. acknowledge China Scholarship Council programme (CSC, scholarship No. 202008060037) for financial support to J.W. The Royal Society is gratefully acknowledged for financial support (IEC\R2\202028). Work at UKHSA was supported by Grant-in-Aid project, Open Innovation in AMR; 113361. Any opinions expressed in the paper are those of the authors and not necessarily UKHSA or the Department for Health and Social Care.
Publisher Copyright:
© 2024 The Authors. Published by American Chemical Society.
PY - 2024/2/8
Y1 - 2024/2/8
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.
UR - http://www.scopus.com/inward/record.url?scp=85182549565&partnerID=8YFLogxK
U2 - 10.1021/acsmedchemlett.3c00460
DO - 10.1021/acsmedchemlett.3c00460
M3 - Article
SN - 1948-5875
VL - 15
SP - 239
EP - 249
JO - Acs Medicinal Chemistry Letters
JF - Acs Medicinal Chemistry Letters
IS - 2
ER -