- New amphiphilic neamine conjugates bearing a metal binding motif active against MDR E.?aerogenes Gram-negative bacteria
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Structure of bacterial envelope is one of the major factors contributing to Gram negative bacterial resistance. To develop new agents that target the bacterial membranes, we synthesized, by analogy with our previous peptide conjugates, new amphiphilic 3′,4′,6-trinaphthylmethylene neamines functionalized at position 5 through a short spacer by a chelating group, tris(2-pyridylmethyl)amine (TPA) and di-(picolyl)amine (DPA) and tetraazacyclotetradecane (Cyclam). ESI+mass spectrometry analyses showed that neither Zn(II)(NeaDPA) nor Cu(II)(NeaCyclam) were stable in the Mueller Hinton (MH) medium used for antibacterial assays. In contrast Zn(NeaTPA) was stable in the MH medium. Interestingly, in MH, the free ligand NeaTPA was found bound to zinc, the zinc salt being the most abundant salt in this medium. Thus, the antibacterial activities of all compounds were evaluated as free ligands against E.?coli strains, wild type AG100 and E.?aerogenes EA289 (a clinical MDR strain that overexpresses AcrAB-TolC efflux pump), as well as AG100A an AcrAB- E.?coli strain and EA298 a TolC- derivative. NeaCyclam and Zn(NeaTPA) were by far the most efficient compounds active against resistant isolate EA289 with MICs in the range 16–4 and 4?μM, respectively, while usual antibiotics such as β-lactams and phenicols were inactive (MICs?>?128) and ciprofloxacin was at 64?μM. Zn(NeaTPA) and NeaCyclam were shown to target and permeabilize the outer membrane of EA289 by promoting the cleavage of nitrocefin by periplasmic β-lactamase. Moreover, all the neamine conjugates were able to block the efflux of 1,2’-dinaphthylamine in EA289, by acting on the efflux transporter located in the inner membrane. These membranotropic properties contribute to explain the activities of these neamine conjugates toward the MDR EA289 strain.
- Allam, Anas,Maigre, Laure,Alves de Sousa, Rodolphe,Dumont, Estelle,Vergalli, Julia,Pagès, Jean-Marie,Artaud, Isabelle
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- Neamine Compositions and Methods of Use Thereof
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Provided herein are compositions containing neamine, or a composition containing an agent that possesses one or more activities of neamine, and the research, diagnostic and therapeutic uses of such compounds, such as for the treatment of cancer.
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Paragraph 0265
(2021/07/24)
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- Neamine and 2-deoxystreptamine neomycin derivatives exhibit antinociceptive activity in rat models of phasic, incision and neuropathic pain
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Objectives To assess the antinociceptive activity of the neomycin derivatives neamine and 2-deoxystreptamine following intraspinal administration in rats. Methods We used the tail-flick test and measured the threshold to mechanical stimulation in models of incisional and neuropathic pain. Key findings The derivatives produced antinociception in the tail-flick test and reduced mechanical allodynia in models of incisional and neuropathic pain. The approximate ED50 in milligrams (confidence limits in parenthesis) in these tests were 1.35 mg (0.61; 2.95), 0.20 mg (0.14; 0.27) and 0.28 mg (0.12; 0.63) for neamine, and 1.05 mg (0.68; 1.60), 0.78 mg (0.776; 0.783) and 0.79 mg (0.46; 1.34) for 2-deoxystreptamine, respectively. Neamine was more potent than 2-deoxystreptamine in the incisional and neuropathic pain models, but they had similar potency in the tail-flick test. Tetra-azidoneamine, a neamine derivative in which free amino groups are replaced with azido groups, did not change the incisional mechanical allodynia. The reduction of incisional allodynia by neamine and 2-deoxystreptamine was transitorily antagonized by intrathecal administration of calcium chloride. Conclusions The intraspinal administration of neamine and 2-deoxystreptamine is antinociceptive in rats. The presence of amino groups in the structure of these derivatives is fundamental to their antinociceptive effect, which may be due to a calcium antagonist activity.
- Prado, Wiliam A.,Rossaneis, Ana C.,Carvalho, Ivone,Zamoner, Luis Otvio B.,Corrado, Alexandre P.
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p. 1696 - 1704
(2016/01/26)
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- Neamine Compositions and Methods of Use Thereof
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Provided herein are compositions containing neamine, or a composition containing an agent that possesses one or more activities of neamine, and the research, diagnostic and therapeutic uses of such compounds, such as for the treatment of cancer.
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- Structure-toxicity relationship of aminoglycosides: Correlation of 2′-amine basicity with acute toxicity in pseudo-disaccharide scaffolds
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A new pseudo-disaccharide NB23 with a 3′,4′-methylidene protection was designed and its properties were evaluated in comparison to other two structurally related pseudo-disaccharides. The basicity of the 2′-amine was found to be well correlated to acute toxicity data in mice: the increase in the basicity is associated with the toxicity increase. Based on these data, a new pseudo-trisaccharide NB45 was constructed. NB45 exhibited significant antibacterial activity while at the same time retained low acute toxicity.
- Chen, Lilach,Hainrichson, Mariana,Bourdetsky, Dmitry,Mor, Amram,Yaron, Sima,Baasov, Timor
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p. 8940 - 8951
(2009/04/03)
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- Design and synthesis of a structurally constrained aminoglycoside
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(Chemical Equation Presented) The synthesis of a constrained tricyclic aminoglycoside derivative is described. This constrained compound fixes the spatial orientation of two critical rings for the minimal motif for binding to biological macromolecules such as RNA and proteins. Methanolysis of neomycin B under acidic conditions produced the bicyclic neamine. Transient protection by the Cu2+ ion and regioselective introduction of protective groups led to intermediate 7, which was used for a key annulation reaction that introduced the tricyclic nucleus into the structural framework. A final hydrogenolysis step to remove the protective groups produced the desired target molecule. The efficient eight-step synthesis was accomplished in 8% overall yield.
- Kling, Dale,Hesek, Dusan,Shi, Qicun,Mobashery, Shahriar
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p. 5450 - 5453
(2008/02/08)
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- Synthesis of (+),(-)-neamine and their positional isomers as potential antibiotics
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The syntheses of (+)-neamine 1, (-)-neamine ent-1 and their positional isomers 2, 3, ent-2 and ent-3 are reported as potential new scaffolds for novel aminoglycoside antibiotics. These isomers exhibit similar inhibitory activities, as shown using an in vitro translation assay. A simple model is proposed to explain this lack of stereospecific binding to the ribosomal RNA.
- Ryu, Do Hyun,Tan, Choon-Hong,Rando, Robert R.
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p. 901 - 903
(2007/10/03)
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- AMINOGLYCOSIDE ANTIBIOTICS AND METHODS OF USING SAME
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The present invention relates to aminoglycoside compounds having antibiotic activity. Moreover, the present invention relates to L-aminoglycoside compounds and diastereomers thereof which posses antibiotic activity and are not susceptible to development of resistant bacterial strains. The present invention also relates to methods of treatment and pharmaceutical compositions that utilize or comprise one or more of aminoglycoside compounds provided by the invention.
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- Synthesis of neamine libraries for RNA recognition using solution phase chemistry
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Selective protection of the 6'-amino group of neamine allows the preparation of aminoglycoside libraries by reductive amination and Ugi multicomponent coupling.
- Nunns, Claire L.,Spence, Lee A.,Slater, Martin J.,Berrisford, David J.
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p. 9341 - 9345
(2007/10/03)
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- Rapid combinatorial synthesis of aminoglycoside antibiotic mimetics: Use of a polyethylene glycol-linked amine and a neamine-derived aldehyde in multiple component condensation as a strategy for the discovery of new inhibitors of the HIV RNA Rev responsive element
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A library of neomycin B mimetics has been prepared rapidly without chromatography using a neamine-derived aldehyde, tert-butyl isocyanide or isocyanoacetic acid methyl ester, a glycine-conjugated polyethylene glycol (PEG) methyl ether, and various Cbz-N-protected amino acids as substrates in a Ugi-type one-pot reaction. The product linked to PEG was isolated by precipitation in ether. A simultaneous base-catalyzed hydrolysis and de-O-acetylation followed by hydrogenation provided an easy access to a library of neomycin B mimetics, which were screened for binding to the Rev responsive element of HIV mRNA (RRE). Several products were found to be more active than neamine with the IC50 values in the micromolar range.
- Park, William K. C.,Auer, Manfred,Jaksche, Herbert,Wong, Chi-Huey
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p. 10150 - 10155
(2007/10/03)
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- 60CO-irradiation as an alternate method for sterilization of Penicillin G, neomycin, novobiocin, and dihydrostreptomycin
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The effects of the use of 60Co-irradiation to sterilize antibiotics were evaluated. The antibiotic powders were only occasionally contaminated with microorganisms. The D-values of the products and environmental isolates were 0.028, 0.027, 0.015, 0.046, 0.15, 0.018, and 0.19 Mrads for Aspergillus species (UC 7297, 7298), A. fumigatus (UC 7299), Rhodotorula species (UC 7300), Penicillium oxalicum (UC 7269), Pseudomonas maltophilia (UC 6855), and a biological indicator microorganism, Bacillus pumilus spores (ATCC 27142). An irradiation dose of 1.14 Mrads, therefore, was sufficient to achieve a six-log cycle destruction of B. pumilus spores. Based on the bioburden data, a minimum irradiation dose of 1.05 Mrads was calculated to be sufficient to obtain a 10-6 probability of sterilizing the most radioresistant isolate, Pen. oxalicum. To determine the radiolytic degradation scheme and the stability of the antibiotics following irradiation, high-performance liquid chromatographic (HPLC) methods were developed. The resulting rates of degradation for the antibiotics were 0.6, 1.2, 2.3, and 0.95%/Mrad for penicillin G, neomycin, novobiocin, and dihydrostreptomycin, respectively. Furthermore, radiolytic degradation pathways for the antibiotics were identified and found to be similar to those commonly encountered when antibiotics are subjected to acidic, basic, hydrolytic, or oxidative treatments. No radiolytic compounds unique to 60Co-irradiation were found.
- Tsuji,Rahn,Steindler
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