Amphiphilic aminoglycoside derivatives are potential new antimicrobial agents mostly developed to fight resistant bacteria. The mechanism of action of the 3',6-dinonyl neamine, one of the most promising derivative, has been investigated on Gram-negative bacteria, including P. aeruginosa. In this study, we have assessed its mechanism of action against Gram-positive bacteria, S. aureus and B. subtilis. By conducting time killing experiments, we assessed the bactericidal effect induced by 3',6-dinonyl neamine on S. aureus MSSA and MRSA. By measuring the displacement of BODIPY™-TR cadaverine bound to lipoteichoic acids (LTA), we showed that 3',6-dinonyl neamine interacts with these bacterial surface components. We also highlighted the ability of 3',6-dinonyl neamine to enhance membrane depolarization and induce membrane permeability, by using fluorescent probes, DiSCC(5) and propidium iodide, respectively. These effects are observed for both MSSA and MRSA S. aureus as well as for B. subtilis. By electronic microscopy, we imaged the disruption of membrane integrity of the bacterial cell wall and by fluorescence microscopy, we demonstrated changes in the localization of lipids from the enriched-septum region and the impairment of the formation of septum. At a glance, we demonstrated that 3',6-dinonyl neamine interferes with multiple targets suggesting a low ability of bacteria to acquire resistance to this agent. In turn, the amphiphilic neamine derivatives are promising candidates for development as novel multitarget therapeutic antibiotics.
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http://dx.doi.org/10.1016/j.bbamem.2019.05.020 | DOI Listing |
ACS Infect Dis
December 2024
Laboratory of Medicinal Chemistry, Department of Chemistry, Clemson University, Clemson, South Carolina 29634, United States.
Worldwide, bacterial antibiotic resistance continues to outpace the level of drug development. One way to counteract this threat to society is to identify novel ways to rapidly screen and identify drug candidates in living cells. Developing fluorescent antibiotics that can enter microorganisms and be displaced by potential antimicrobial compounds is an important but challenging endeavor due to the difficulty in entering bacterial cells.
View Article and Find Full Text PDFMicrobiol Spectr
November 2024
UCLouvain, Louvain Drug Research Institute, Cellular & Molecular Pharmacology, Brussels, Belgium.
Oncol Res
June 2023
School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China.
This research aimed to explore the influence of Src homology-2 containing protein tyrosine phosphatase (SHP-2) on the functions of tyrosine kinase receptors with immunoglobulin and EGF homology domains 2 (Tie2)-expressing monocyte/macrophages (TEMs) and the influence of the angiopoietin(Ang)/Tie2-phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) (Ang/Tie2-PI3K/Akt/mTOR) signaling pathway on the tumor microvascular remodeling in an immunosuppressive microenvironment. , SHP-2-deficient mice were used to construct colorectal cancer (CRC) liver metastasis models. SHP-2-deficient mice had significantly more metastatic cancer and inhibited nodules on the liver surface than wild-type mice, and the high-level expression of p-Tie2 was found in the liver tissue of the macrophages' specific SHP-2-deficient mice (SHP-2MAC-KO) + planted tumor mice.
View Article and Find Full Text PDFInt J Mol Sci
December 2022
Department of Bioengineering, Imperial College London, London SW7 2BP, UK.
Angiogenesis, the growth of new blood vessels, is a critical factor of carcinogenesis. Neomycin and neamine, two drugs blocking the nuclear translocation of angiogenin (ANG), have been proven to inhibit tumour growth in vivo. However, the high toxicity of neomycin prevents its therapeutic use, thus indicating that the less toxic neamine may be a better candidate.
View Article and Find Full Text PDFChin J Nat Med
November 2022
School of Pharmaceutical Sciences, Peking University, Beijing 100191, China. Electronic address:
For the purpose of seeking new antibiotics, researchers usually modify the already-existing ones. However, this strategy has been extensively used and is close to its limits, especially in the case of aminoglycosides, and it is difficult to find a proper aminoglycoside antibiotic for novel modification. In this paper, we reported the design, synthesis, and evaluation of a series of 5-epi-neamine derivatives based on the structural information of bacterial 16S RNA A-site binding with aminoglycosides.
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