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Jean-luc Décout - One of the best experts on this subject based on the ideXlab platform.
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antimicrobial activity of amphiphilic Neamine derivatives understanding the mechanism of action on gram positive bacteria
Biochimica et Biophysica Acta, 2019Co-Authors: Jitendriya Swain, Jean-luc Décout, Florian Briée, Micheline El Khoury, Aurelien Flament, Clement Dezanet, Patrick Van Der Smissen, Mariepaule MingeotleclercqAbstract:Abstract 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, DiSC3C(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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Broad-spectrum antibacterial amphiphilic aminoglycosides: A new focus on the structure of the lipophilic groups extends the series of active dialkyl Neamines.
European Journal of Medicinal Chemistry, 2018Co-Authors: Louis Zimmermann, Julie Kempf, Florian Briée, Jitendriya Swain, Marie-paule Mingeot-leclercq, Jean-luc DécoutAbstract:Abstract Amphiphilic aminoglycosides (AAGs) constitute a new class of antibacterial compounds targeting the bacterial membranes. We have identified the 3′,6-dinonyl Neamine 9 as a broad spectrum antibacterial AAG. Here, we report on the synthesis, antibacterial activity and eukaryotic cytotoxicity of new 3′,6-dialkyl Neamines designed in order to finely delineate the structure-activity relationships relating their activity to a lipophilicity window. New broad-spectrum antibacterial derivatives were obtained carrying two identical linear or branched alkyl groups or two different linear alkyl groups. Two fluorescent antibacterial 3′,6-heterodialkyl Neamines carrying a pyrenylbutyl fluorophore were also identified as potential tools for mechanistic study. Homodialkyl and heterodialkyl Neamines appeared to be more active on Gram-negative bacteria than dinaphthylalkyl Neamines. However, branched dialkyl Neamines or heterodialkyl derivatives were found to be more cytotoxic on mammalian cells than 9. The exposure of P. aeruginosa over one month to half-MIC of one of the most active derivatives 9 demonstrated the high difficulty of resistance emergence to AAGs.
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new broad spectrum antibacterial amphiphilic aminoglycosides active against resistant bacteria from Neamine derivatives to smaller neosamine analogues
Journal of Medicinal Chemistry, 2016Co-Authors: Louis Zimmermann, Jérôme Désiré, Guillaume Sautrey, Mariepaule Mingeotleclercq, Micheline El Khoury, R Vinicius S Barros, Jean-luc DécoutAbstract:Aminoglycosides (AGs) constitute a major family of potent and broad-spectrum antibiotics disturbing protein synthesis through binding to the A site of 16S rRNA. Decades of widespread clinical use of AGs strongly reduced their clinical efficacy through the selection of resistant bacteria. Recently, conjugation of lipophilic groups to AGs generated a novel class of potent antibacterial amphiphilic aminoglycosides (AAGs) with significant improved activities against various sensitive and resistant bacterial strains. We have identified amphiphilic 3′,6-dialkyl derivatives of the small aminoglycoside Neamine as broad spectrum antibacterial agents targeting bacterial membranes. Here, we report on the synthesis and the activity against sensitive and resistant Gram-negative and/or Gram-positive bacteria of new amphiphilic 3′,4′-dialkyl Neamine derivatives and of their smaller analogues in the 6-aminoglucosamine (neosamine) series prepared from N-acetylglucosamine.
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new amphiphilic Neamine derivatives active against resistant pseudomonas aeruginosa and their interactions with lipopolysaccharides
Antimicrobial Agents and Chemotherapy, 2014Co-Authors: Guillaume Sautrey, Jean-luc Décout, Louis Zimmermann, Magali Deleu, Alicia Delbar, Luiza Souza Machado, Katy Jeannot, Francoise Van Bambeke, Julien M Buyck, Mariepaule MingeotleclercqAbstract:The development of novel antimicrobial agents is urgently required to curb the widespread emergence of multidrug-resistant bacteria like colistin-resistant Pseudomonas aeruginosa. We previously synthesized a series of amphiphilic Neamine derivatives active against bacterial membranes, among which 3=,6-di-O-[(2-naphthyl)propyl]Neamine (3=,6-di2NP), 3=,6-di-O-[(2-naphthyl)butyl]Neamine (3=,6-di2NB), and 3=,6-di-O-nonylNeamine (3=,6-diNn) showed high levels of activity and low levels of cytotoxicity (L. Zimmermann et al., J. Med. Chem. 56:7691–7705, 2013). We have now further characterized the activity of these derivatives against colistin-resistant P. aeruginosa and studied their mode of action; specifically, we characterized their ability to interact with lipopolysaccharide (LPS) and to alter the bacterial outer membrane (OM). The three amphiphilic Neamine derivatives were active against clinical colistin-resistant strains (MICs, about 2 to 8 g/ml), The most active one (3=,6-diNn) was bactericidal at its MIC and inhibited biofilm formation at 2-fold its MIC. They cooperatively bound to LPSs, increasing the outer membrane permeability. Grafting long and linear alkyl chains (nonyl) optimized binding to LPS and outer membrane permeabilization. The effects of amphiphilic Neamine derivatives on LPS micelles suggest changes in the cross-bridging of lipopolysaccharides and disordering in the hydrophobic core of the micelles. The molecular shape of the 3=,6-dialkyl Neamine derivatives induced by the nature of the grafted hydrophobic moieties (naphthylalkyl instead of alkyl) and the flexibility of the hydrophobic moiety are critical for their fluidifying effect and their ability to displace cations bridging LPS. Results from this work could be exploited for the development of new amphiphilic Neamine derivatives active against colistin-resistant P. aeruginosa.
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tuning the antibacterial activity of amphiphilic Neamine derivatives and comparison to paromamine homologues
Journal of Medicinal Chemistry, 2013Co-Authors: Louis Zimmermann, Isabelle Baussanne, Myriam Ouberai, Antoine Bussière, Mariepaule Mingeotleclercq, Claude Jolivalt, Jean-luc DécoutAbstract:Aminoglycosides are antibiotic drugs that act through binding to rRNA. In the search for antimicrobial amphiphilic aminoglycosides targeting bacterial membranes, we report here on the discovery of three dialkyl derivatives of the small aminoglycoside Neamine active against susceptible and resistant Gram-positive and Gram-negative bacteria. One of these derivatives (R = 2-naphthylpropyl), which has good activity against MRSA and VRSA, showed a low toxicity in eukaryotic cells at 10 μM. The synthesis of amphiphilic paromamine and Neamine homologous derivatives pointed out the role of the 6'-amine function of the Neamine core in the antibacterial effects. The optimal number of lipophilic substituents to be attached to the Neamine core and the corresponding required lipophilicity determined here should permit a more selective targeting of bacterial membranes relative to eukaryotic membranes. This work revealed the existence of windows of lipophilicity necessary for obtaining strong antibacterial effects that should be of interest in the field of antibacterial amphiphilic aminoglycosides.
Guofu Hu - One of the best experts on this subject based on the ideXlab platform.
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sub chronic 90 day toxicity of Neamine in sd rats and its anti liver cancer activity in vitro and in vivo
Toxicology and Applied Pharmacology, 2017Co-Authors: Yanli Wu, Guofu Hu, Yongdong Feng, Yanling Li, Yiping Xu, Yunxia WuAbstract:Abstract Neamine, an inhibitor of angiogenin (ANG), is a new investigative anticancer drug currently in preclinical stage. Here we report the 90-day sub-chronic toxicity of Neamine in SD rats and its anti-liver cancer activity in vitro and in vivo. Neamine has a No Observed Adverse Effect Level (NOAEL) of 12 and 16 mg·kg− 1·d− 1 for female and male rats, respectively. No mortality was found. The adverse effects included increased organ coefficients of spleen and kidney, increased BUN in both female and male rats at high dose, increased CR and decreased organ coefficients of heart and liver in male rats at high dose. All of which, except the kidney coefficient and BUN in males, returned to normal levels after 28-day recovery. Histopathological examination revealed vacuolar degeneration of glomerulus, degeneration of renal tubules and cast in the kidneys, which were also recovered except in males of high-dosing group. These results indicate that kidney is the most susceptible organ for Neamine toxicity. Tissue microarray analysis validated that ANG is up-regulated in hepatocellular carcinoma accompanied by increased nuclear translocation, suggesting that ANG is a possible target for drug development in liver cancer treatment. Neamine blocked nuclear translocation of ANG in HUVEC and HepG2 cells, and inhibited ANG-stimulated cell proliferation without affecting basal level cell proliferation. Neamine also inhibited progression of HepG2 xenografts in athymic mice accompanied by decreased angiogenesis and cancer cell proliferation. These results suggest that Neamine is a specific ANG inhibitor with low toxicity and high anti-liver cancer efficacy.
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Neamine inhibits growth of pancreatic cancer cells in vitro and in vivo
Journal of Huazhong University of Science and Technology-medical Sciences, 2016Co-Authors: Yanli Wu, Guofu Hu, Xiaoyan Zhang, Yunxia WuAbstract:Neamine, a non-toxic derivative of neomycin, has recently been shown to have antitumor activities in various types of cancers. However, its effect on pancreatic cancer is still unknown. The study aimed to investigate its antitumor activity on pancreatic cancer and the underlying mechanisms. MTT assay was used to observe the effect of Neamine on angiogenin (ANG)-induced AsPC-1 cell proliferation. Tissue microassay and immunofluorescence staining were used to detect the expression of ANG and its nuclear translocation, respectively. Tumor xenografts were established by subcutaneous inoculation of AsPC-1 pancreatic cancer cells into the right flanks of nude mice, and Neamine was injected subcutaneously. Immunohistochemistry was done to observe the expression of ANG, CD31 and Ki-67 in tumor xenografts. It was found that Neamine blocked the nuclear translocation of ANG effectively and inhibited ANG-induced AsPC-1 cell proliferation in a dose-dependent manner. Neamine had anti-tumor effects on AsPC-1 xenograft models. Consistently, Neamine reduced the expression levels of ANG, Ki-67 and CD31 in tumor xenografts. It was concluded that Neamine may be a promising agent for treatment of pancreatic cancer.
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Neamine is preferential as an anti prostate cancer reagent by inhibiting cell proliferation and angiogenesis with lower toxicity than cis platinum
Oncology Letters, 2015Co-Authors: Guofu Hu, Yunxia WuAbstract:Hormone therapy is the most commonly used treatment for prostate cancer, but for androgen-independent cancer, few effective treatment methods are available. Therefore, the requirement to develop novel and effective anti-prostate cancer drugs is extremely urgent. Angiogenin has been suggested as a molecular target for prostate cancer treatment; its overexpression contributes to androgen-dependent prostate cancer growth and castration-resistant growth of androgen-independent prostate cancer. The aim of the present study was to investigate whether Neamine, a low toxicity angiogenin nuclear translocation inhibitor, has preferential anti-prostate cancer activity compared with cis-platinum (DDP) and the mechanisms involved. Immunofluorescence and MTT assays were used to observe the effect of Neamine on the nuclear translocation of angiogenin and cell proliferation, and a PC-3 cell transplanted tumor model was used to investigate the in vivo activity of Neamine and DDP. Immunohistochemistry was performed to observe the expression of angiogenin, cluster of differentiation (CD)31 and Ki-67. It was found that Neamine blocked nuclear translocation of angiogenin effectively and inhibited angiogenin-induced human umbilical vein endothelial cell and PC-3 cell proliferation in a dose-dependent manner. Neamine exerted a comparative antitumor effect, but lower toxicity (weight loss), in the PC-3 xenograft models treated with DDP. Neamine consistently reduced the expression of angiogenin and CD31 significantly, but no difference was found in Ki-67 expression compared with DDP. These data suggested that Neamine may be a promising agent for prostate cancer treatment.
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pharmacokinetics of Neamine in rats and anti cervical cancer activity in vitro and in vivo
Cancer Chemotherapy and Pharmacology, 2015Co-Authors: Xiaoyan Zhang, Guofu Hu, Yanli Wu, Songlin An, Yunxia WuAbstract:Objective To study the pharmacokinetics of Neamine in rats and to evaluate its anti-cervical cancer activity.
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Neamine inhibits oral cancer progression by suppressing angiogenin mediated angiogenesis and cancer cell proliferation
Anticancer Research, 2014Co-Authors: Koji Kishimoto, Shoko Yoshida, Soichiro Ibaragi, Norie Yoshioka, Guofu Hu, Akira SasakiAbstract:Background: Angiogenin undergoes nuclear translocation and stimulates ribosomal RNA transcription in both endothelial and cancer cells. Consequently, angiogenin has a dual effect on cancer progression by inducing both angiogenesis and cancer cell proliferation. The aim of this study was to assess whether Neamine, a blocker of nuclear translocation of angiogenin, possesses antitumor activity toward oral cancer. Materials and Methods: The antitumor effect of Neamine on oral cancer cells was examined both in vitro and in vivo. Results: Neamine inhibited the proliferation of HSC-2, but not that of SAS oral cancer cells in vitro. Treatment with Neamine effectively inhibited growth of HSC-2 and SAS cell xenografts in athymic mice. Neamine treatment resulted in a significant decrease in tumor angiogenesis, accompanied by a decrease in angiogenin- and proliferating cell nuclear antigen-positive cancer cells, especially of HSC-2 tumors. Conclusion: Neamine effectively inhibits oral cancer progression through inhibition of tumor angiogenesis. Neamine also directly inhibits proliferation of certain types of oral cancer cells. Therefore, Neamine has potential as a lead compound for oral cancer therapy.
Louis Zimmermann - One of the best experts on this subject based on the ideXlab platform.
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Broad-spectrum antibacterial amphiphilic aminoglycosides: A new focus on the structure of the lipophilic groups extends the series of active dialkyl Neamines.
European Journal of Medicinal Chemistry, 2018Co-Authors: Louis Zimmermann, Julie Kempf, Florian Briée, Jitendriya Swain, Marie-paule Mingeot-leclercq, Jean-luc DécoutAbstract:Abstract Amphiphilic aminoglycosides (AAGs) constitute a new class of antibacterial compounds targeting the bacterial membranes. We have identified the 3′,6-dinonyl Neamine 9 as a broad spectrum antibacterial AAG. Here, we report on the synthesis, antibacterial activity and eukaryotic cytotoxicity of new 3′,6-dialkyl Neamines designed in order to finely delineate the structure-activity relationships relating their activity to a lipophilicity window. New broad-spectrum antibacterial derivatives were obtained carrying two identical linear or branched alkyl groups or two different linear alkyl groups. Two fluorescent antibacterial 3′,6-heterodialkyl Neamines carrying a pyrenylbutyl fluorophore were also identified as potential tools for mechanistic study. Homodialkyl and heterodialkyl Neamines appeared to be more active on Gram-negative bacteria than dinaphthylalkyl Neamines. However, branched dialkyl Neamines or heterodialkyl derivatives were found to be more cytotoxic on mammalian cells than 9. The exposure of P. aeruginosa over one month to half-MIC of one of the most active derivatives 9 demonstrated the high difficulty of resistance emergence to AAGs.
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new broad spectrum antibacterial amphiphilic aminoglycosides active against resistant bacteria from Neamine derivatives to smaller neosamine analogues
Journal of Medicinal Chemistry, 2016Co-Authors: Louis Zimmermann, Jérôme Désiré, Guillaume Sautrey, Mariepaule Mingeotleclercq, Micheline El Khoury, R Vinicius S Barros, Jean-luc DécoutAbstract:Aminoglycosides (AGs) constitute a major family of potent and broad-spectrum antibiotics disturbing protein synthesis through binding to the A site of 16S rRNA. Decades of widespread clinical use of AGs strongly reduced their clinical efficacy through the selection of resistant bacteria. Recently, conjugation of lipophilic groups to AGs generated a novel class of potent antibacterial amphiphilic aminoglycosides (AAGs) with significant improved activities against various sensitive and resistant bacterial strains. We have identified amphiphilic 3′,6-dialkyl derivatives of the small aminoglycoside Neamine as broad spectrum antibacterial agents targeting bacterial membranes. Here, we report on the synthesis and the activity against sensitive and resistant Gram-negative and/or Gram-positive bacteria of new amphiphilic 3′,4′-dialkyl Neamine derivatives and of their smaller analogues in the 6-aminoglucosamine (neosamine) series prepared from N-acetylglucosamine.
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new amphiphilic Neamine derivatives active against resistant pseudomonas aeruginosa and their interactions with lipopolysaccharides
Antimicrobial Agents and Chemotherapy, 2014Co-Authors: Guillaume Sautrey, Jean-luc Décout, Louis Zimmermann, Magali Deleu, Alicia Delbar, Luiza Souza Machado, Katy Jeannot, Francoise Van Bambeke, Julien M Buyck, Mariepaule MingeotleclercqAbstract:The development of novel antimicrobial agents is urgently required to curb the widespread emergence of multidrug-resistant bacteria like colistin-resistant Pseudomonas aeruginosa. We previously synthesized a series of amphiphilic Neamine derivatives active against bacterial membranes, among which 3=,6-di-O-[(2-naphthyl)propyl]Neamine (3=,6-di2NP), 3=,6-di-O-[(2-naphthyl)butyl]Neamine (3=,6-di2NB), and 3=,6-di-O-nonylNeamine (3=,6-diNn) showed high levels of activity and low levels of cytotoxicity (L. Zimmermann et al., J. Med. Chem. 56:7691–7705, 2013). We have now further characterized the activity of these derivatives against colistin-resistant P. aeruginosa and studied their mode of action; specifically, we characterized their ability to interact with lipopolysaccharide (LPS) and to alter the bacterial outer membrane (OM). The three amphiphilic Neamine derivatives were active against clinical colistin-resistant strains (MICs, about 2 to 8 g/ml), The most active one (3=,6-diNn) was bactericidal at its MIC and inhibited biofilm formation at 2-fold its MIC. They cooperatively bound to LPSs, increasing the outer membrane permeability. Grafting long and linear alkyl chains (nonyl) optimized binding to LPS and outer membrane permeabilization. The effects of amphiphilic Neamine derivatives on LPS micelles suggest changes in the cross-bridging of lipopolysaccharides and disordering in the hydrophobic core of the micelles. The molecular shape of the 3=,6-dialkyl Neamine derivatives induced by the nature of the grafted hydrophobic moieties (naphthylalkyl instead of alkyl) and the flexibility of the hydrophobic moiety are critical for their fluidifying effect and their ability to displace cations bridging LPS. Results from this work could be exploited for the development of new amphiphilic Neamine derivatives active against colistin-resistant P. aeruginosa.
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tuning the antibacterial activity of amphiphilic Neamine derivatives and comparison to paromamine homologues
Journal of Medicinal Chemistry, 2013Co-Authors: Louis Zimmermann, Isabelle Baussanne, Myriam Ouberai, Antoine Bussière, Mariepaule Mingeotleclercq, Claude Jolivalt, Jean-luc DécoutAbstract:Aminoglycosides are antibiotic drugs that act through binding to rRNA. In the search for antimicrobial amphiphilic aminoglycosides targeting bacterial membranes, we report here on the discovery of three dialkyl derivatives of the small aminoglycoside Neamine active against susceptible and resistant Gram-positive and Gram-negative bacteria. One of these derivatives (R = 2-naphthylpropyl), which has good activity against MRSA and VRSA, showed a low toxicity in eukaryotic cells at 10 μM. The synthesis of amphiphilic paromamine and Neamine homologous derivatives pointed out the role of the 6'-amine function of the Neamine core in the antibacterial effects. The optimal number of lipophilic substituents to be attached to the Neamine core and the corresponding required lipophilicity determined here should permit a more selective targeting of bacterial membranes relative to eukaryotic membranes. This work revealed the existence of windows of lipophilicity necessary for obtaining strong antibacterial effects that should be of interest in the field of antibacterial amphiphilic aminoglycosides.
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synthese et evaluation de derives amphiphiles de la Neamine et de la neosamine projet nea et neo
2012Co-Authors: Louis ZimmermannAbstract:Apres la mise en evidence de la forte activite antibacterienne a large spectre contre des bacteries Gram (+) et Gram (-) sauvages et resistantes aux antibiotiques des derives 3',4',6-tri-naphtylmethyl (2NM) et -trihexyl d'un petit aminoglycoside, la Neamine, et de l'activite, contre les bacteries Gram (+) sauvages et resistantes, des 3',4'- et 3',6-di2NM Neamines, les travaux realises ont cherche a obtenir des derives antibacteriens plus actifs et moins toxiques que les derives trialkyles. Deux approches en series aminoglycosides amphiphiles ont ete developpees dans ce but : (1) la synthese a partir de la neomycine B de nouveaux derives de la Neamine portant des groupements alkyles de differentes lipophilies de facon a diminuer globalement celle-ci et (2) apres les premiers resultats en serie Neamine, la synthese a partir de la N-acetyl glucosamine de derives amphiphiles d'un des constituants de la Neamine, la neosamine.Dans la premiere approche, apres la mise au point de methodes d'alkylation de la Neamine, il a ete possible de passer de derives trialkyles de la Neamine a des derives dialkyles, en particulier 3',6- dialkyles, plus actifs et moins cytotoxiques ceci en diminuant la lipophilie globale des composes. Dans la deuxieme approche, a partir de la 1-allyl 3,4-dinonyl neosamine, des derives amphiphiles antibacteriens a large spectre portant en position anomerique des groupements polaires ont ete prepares apres epoxydation de la double liaison. Le derive tri2NM de la Neamine s'etait avere avoir une forte affinite pour les lipopolysaccharides de la membrane externe de P. aeruginosa et agir a travers son caractere amphiphiles pour depolariser la membrane bacterienne. L'etude du mode d'action des derives de la Neamine prepares les plus actifs a suggere un mecanisme d'action similaire.
Keita Hamasaki - One of the best experts on this subject based on the ideXlab platform.
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Nucleobase modified Neamines with a lysine as a linker, their inhibition specificity for TAR-Tat derived from HIV-1.
Bioorganic & Medicinal Chemistry, 2015Co-Authors: Ryo Inoue, Kentarou Watanabe, Toyofusa Katou, Yasunori Ikezawa, Keita HamasakiAbstract:Abstract Nucleobase modified Neamines with a lysine as the linker (NbK-Neamines) were synthesized and their binding toward hairpin RNAs derived from HIV-1 activator region were studied. NbK-Neamines were bind those RNAs with micro molar level of binding affinities and compete with corresponding activator peptide for TAR RNA, but not for RRE RNA. GbK-Neamine denotes the highest binding affinity with TAR RNA, three to five times higher than other three NbK-Neamines. GbK-Neamine could be a candidate of potential inhibitor for TAR-Tat.
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Nucleobase modified Neamines, their synthesis and binding specificity for HIV TAR RNA.
Nucleic Acids Symposium Series, 2007Co-Authors: Kenatarou Watanabe, Toyofusa Katou, Yasunori Ikezawa, Saki Yajima, Hirohito Shionoya, Takashi Akagi, Keita HamasakiAbstract:: Twenty Neamine derivatives having a nucleobase, adenine, cytosine, guanine or thimine with a lysine or an argine as a linker and, also, without linker were synthesized and their binding specificity for HIV TAR RNA was studied. Any nucleobase modification on Neamine enhanced their binding affinities for TAR RNA. The binding affinity of Neamine derivatives having a nucleobase at the closer position to Neamine does not depend on the base, but having farther position has shown base specificity for TAR binding.
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Neamine derivatives having a nucleobase with a lysine or an arginine as a linker their synthesis and evaluation as potential inhibitors for hiv tar tat
Bioorganic & Medicinal Chemistry, 2006Co-Authors: Saki Yajima, Hirohito Shionoya, Takashi Akagi, Keita HamasakiAbstract:Abstract Neamine derivatives bearing a nucleobase, adenine, cytosine, guanine or thymine with a lysine or an arginine as a linker have been synthesized and its potential as the inhibitor for HIV TAR–Tat interaction examined. Among them, modified Neamine having an arginine-nucleobase showed a higher inhibition than that of the one having a lysine-nucleobase. The difference of the nucleobase anchor did not characterize inhibition specificity. Also, stereochemistry of the amino acid in the compounds causes no difference in the inhibition for TAR–Tat.
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an aminoglycoside antibiotic Neamine and its aromatic ring substituted derivatives as potential inhibitors for hiv 1 rre rev
Tetrahedron Letters, 2000Co-Authors: Keita Hamasaki, Akihiko UenoAbstract:Abstract The binding affinities of ten aminoglycosides with RRE IIB RNA have been determined. Neamine was found as the simplest consensus unit of aminoglycoside antibiotics that bind RRE IIB RNA tightly. Various aromatic ring-substituted Neamines have been prepared and their binding with RRE IIB RNA was examined. Among them, pyrene-substituted Neamine has shown a submicromolar level of binding with the RNA.
Isabelle Baussanne - One of the best experts on this subject based on the ideXlab platform.
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tuning the antibacterial activity of amphiphilic Neamine derivatives and comparison to paromamine homologues
Journal of Medicinal Chemistry, 2013Co-Authors: Louis Zimmermann, Isabelle Baussanne, Myriam Ouberai, Antoine Bussière, Mariepaule Mingeotleclercq, Claude Jolivalt, Jean-luc DécoutAbstract:Aminoglycosides are antibiotic drugs that act through binding to rRNA. In the search for antimicrobial amphiphilic aminoglycosides targeting bacterial membranes, we report here on the discovery of three dialkyl derivatives of the small aminoglycoside Neamine active against susceptible and resistant Gram-positive and Gram-negative bacteria. One of these derivatives (R = 2-naphthylpropyl), which has good activity against MRSA and VRSA, showed a low toxicity in eukaryotic cells at 10 μM. The synthesis of amphiphilic paromamine and Neamine homologous derivatives pointed out the role of the 6'-amine function of the Neamine core in the antibacterial effects. The optimal number of lipophilic substituents to be attached to the Neamine core and the corresponding required lipophilicity determined here should permit a more selective targeting of bacterial membranes relative to eukaryotic membranes. This work revealed the existence of windows of lipophilicity necessary for obtaining strong antibacterial effects that should be of interest in the field of antibacterial amphiphilic aminoglycosides.
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Major increases of the reactivity and selectivity in aminoglycoside O-alkylation due to the presence of fluoride ions
Tetrahedron, 2012Co-Authors: Olivier Jackowski, Isabelle Baussanne, Marie-paule Mingeot-leclercq, Antoine Bussière, Eric Peyrin, Cécile Vanhaverbeke, Jean-luc DécoutAbstract:Major increases of the selectivity and/or reactivity in aminosugar and sugar O-alkylation were observed in the presence of tetrabutylammonium fluoride (TBAF) in comparison to TBAI under phase-transfer conditions or in solution. The presence of TBAF allowed the selective and rapid alkylation of the 6-hydroxyl function of Neamine and efficient preparation of protected intermediates useful in synthesis and potent or potential antimicrobial O-alkylated derivatives of Neamine and paromamine. In regard to the observed strong effects of TBAF, the alkylation and acylation of carbohydrates merit to be studied in the presence of TBAF under phase-transfer conditions.
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The Pseudomonas aeruginosa membranes: A target for a new amphiphilic aminoglycoside derivative?
Biochimica et Biophysica Acta, 2011Co-Authors: Myriam Ouberai, Isabelle Baussanne, Farid El Garch, Antoine Bussière, Mickael Riou, David Alsteens, Laurence Lins, Yves F. Dufrêne, Robert Brasseur, Jean-luc DécoutAbstract:Aminoglycosides are among the most potent antimicrobials to eradicate Pseudomonas aeruginosa. However, the emergence of resistance has clearly led to a shortage of treatment options, especially for critically ill patients. In the search for new antibiotics, we have synthesized derivatives of the small aminoglycoside, Neamine. The amphiphilic aminoglycoside 3',4',6-tri-2-naphtylmethylene Neamine (3',4',6-tri-2NM Neamine) has appeared to be active against sensitive and resistant P. aeruginosa strains as well as Staphylococcus aureus strains (Baussanne et al., 2010). To understand the molecular mechanism involved, we determined the ability of 3',4',6-tri-2NM Neamine to alter the protein synthesis and to interact with the bacterial membranes of P. aeruginosa or models mimicking these membranes. Using atomic force microscopy, we observed a decrease of P. aeruginosa cell thickness. In models of bacterial lipid membranes, we showed a lipid membrane permeabilization in agreement with the deep insertion of 3',4',6-tri-2NM Neamine within lipid bilayer as predicted by modeling. This new amphiphilic aminoglycoside bound to lipopolysaccharides and induced P. aeruginosa membrane depolarization. All these effects were compared to those obtained with Neamine, the disubstituted Neamine derivative (3',6-di-2NM Neamine), conventional aminoglycosides (neomycin B and gentamicin) as well as to compounds acting on lipid bilayers like colistin and chlorhexidine. All together, the data showed that naphthylmethyl Neamine derivatives target the membrane of P. aeruginosa. This should offer promising prospects in the search for new antibacterials against drug- or biocide-resistant strains.
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synthesis and antimicrobial evaluation of amphiphilic Neamine derivatives
Journal of Medicinal Chemistry, 2010Co-Authors: Isabelle Baussanne, Myriam Ouberai, Antoine Bussière, Mickael Riou, Somnath Halder, Eric Ennifar, Mariepaule Mingeotleclercq, Carine Ganemelbaz, Jeanmarc Paris, Jean-luc DécoutAbstract:The aminoglycoside antibiotics bind to the 16S bacterial rRNA and disturb the protein synthesis. One to four hydroxyl functions of the small aminoglycoside Neamine were capped with phenyl, naphthyl, pyridyl, or quinolyl rings. The 3',4- (6), 3',6- (7a), and the 3',4',6- (10a) 2-naphthylmethylene derivatives appeared to be active against sensitive and resistant Staphylococcus aureus strains. 10a also showed marked antibacterial activities against Gram (-) bacteria, including strains expressing enzymes modifying aminoglycosides, efflux pumps, or rRNA methylases. 7a and 10a revealed a weak and aspecific binding to a model bacterial 16S rRNA. Moreover, its compared to neomycin B, 10a showed a lower ability to decrease H-3 leucine incorporation into proteins in Pseudomonas aeruginosa. All together, out, results suggest that the 3',4,6-tri-2-naphthylmethylene Neamine derivative 10a should act against Gram (-) bacteria through it mechanism different from inhibition of protein synthesis, probably by membrane destabilization.
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synthesis and transfection properties of a series of lipidic Neamine derivatives
Bioconjugate Chemistry, 2009Co-Authors: Tony Le Gall, Isabelle Baussanne, Somnath Halder, Nathalie Carmoy, Tristan Montier, Pierre Lehn, Jean-luc DécoutAbstract:With the view to develop novel bioinspired nonviral vectors for gene delivery, we synthesized a series of cationic lipids with a Neamine headgroup, which incorporates rings I and II of the natural antibiotic aminoglycoside neomycin B. Indeed, we reasoned that Neamine might constitute a straightforward and versatile building block for synthesizing a variety of lipophilic aminoglycosides and modulating their characteristics such as size, topology, lipophilicity, number of charges, and charge density. Neamine derivatives bearing long dialkyl chains, one or two Neamine headgroups, and four to ten protonatable amine functions were prepared through the selective alkylation of the 4′- or 5-hydroxyl function in ring I and ring II of Neamine, respectively. The transfection activity of the twelve derivatives synthesized was investigated in vitro in gene transfection experiments using several mammalian cell lines. The results allowed us to unveil interesting structure−activity relationships and to identify a formula...
