RESUMEN

Magnetic resonance imaging (MRI) is a powerful diagnostic technique that can penetrate deep into tissue providing excellent spatial resolution without the need for ionizing radiation or harmful radionuclides. However, diagnosing bacterial infections in vivo with clinical MRI is severely hampered by the lack of contrast agents with high relaxivity, targeting capabilities, and bacterial penetration and specificity. Here, we report the development of the first gadolinium (Gd)-based bacteria-specific targeting MRI contrast agent, probe 1, by conjugating neomycin, an aminoglycoside antibiotic, with Dotarem (Gd-DOTA, an FDA approved T1-weighted MRI contrast agent). The T1 relaxivity of probe 1 was found to be comparable to that of Gd-DOTA; additionally, probe 1-treated bacteria generated a significantly brighter T1-weighted MR signal than Gd-DOTA-treated bacteria. More importantly, in vitro cellular studies and preliminary in vivo MRI demonstrated probe 1 exhibits the ability to efficiently target bacteria over macrophage-like cells, indicating its great potential for high-resolution imaging of bacterial infections in vivo.

Asunto(s)

Antibacterianos/química , Infecciones Bacterianas/diagnóstico por imagen , Medios de Contraste/química , Compuestos Heterocíclicos/química , Imagen por Resonancia Magnética/métodos , Neomicina/análogos & derivados , Compuestos Organometálicos/química , Animales , Antibacterianos/síntesis química , Medios de Contraste/síntesis química , Escherichia coli/aislamiento & purificación , Infecciones por Escherichia coli/diagnóstico por imagen , Compuestos Heterocíclicos/síntesis química , Masculino , Ratones , Ratones Endogámicos C57BL , Neomicina/síntesis química , Compuestos Organometálicos/síntesis química , Células RAW 264.7 , Infecciones Estafilocócicas/diagnóstico por imagen , Staphylococcus aureus/aislamiento & purificación

RESUMEN

We report the synthesis of multivalent oleanolic acid (OA) protein conjugates as nonglycosylated neomucin mimic for the capture and entry inhibition of influenza viruses. Oleanolic acid derivatives bearing an amine-terminated linker were synthesized by esterification of carboxylic acid and further grafted onto the human serum albumin (HSA) via diethyl squarate method. The binding of hemagglutinin (HA) on the virion surface to the synthetic neomucin was evaluated by hemagglutination inhibition assay. The influenza virus capture ability of the PEGylated OA-HSA conjugate was further investigated by Dynamic Light Scattering (DLS), virus capture assay and Isothermal Titration Calorimeter (ITC) techniques. The pronounced agglutination of viral particles, the high capture efficiency and affinity constant indicate that this neoprotein is comparable to natural glycosylated mucin, suggesting that this material could potentially be used as anti-infective barriers to prevent virus from invading host cells. The study also rationalizes the feasibility of antiviral drug development based on OA or other antiviral small molecules conjugated protein strategies.

Asunto(s)

Antivirales/farmacología , Neomicina/farmacología , Ácido Oleanólico/farmacología , Orthomyxoviridae/efectos de los fármacos , Albúmina Sérica/metabolismo , Antivirales/síntesis química , Antivirales/química , Relación Dosis-Respuesta a Droga , Glicosilación , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Neomicina/síntesis química , Neomicina/química , Ácido Oleanólico/química , Albúmina Sérica/química , Relación Estructura-Actividad

RESUMEN

RNA interference (RNAi) is a promising tool to regulate gene expression by external double stranded RNAs (dsRNAs) such as siRNAs. As an efficient method to deliver siRNAs to liver cells, we propose a novel strategy using vitamin E (VE)-conjugated neomycin derivatives. With the aim of delivering RNAi-based drugs to liver cells, several tripod-type and prodrug-type neomycin derivatives were synthesized, all of which were thermodynamically stabilized RNA duplexes. The prodrug-type derivative 7 and the tripod-type derivative 10 were delivered to liver cancer cells and successfully induced RNAi activity. These results indicated the potential use of natural aminoglycosides as carriers of RNAi drugs.

Asunto(s)

Neomicina/análogos & derivados , Neomicina/síntesis química , ARN Interferente Pequeño/administración & dosificación , ARN Interferente Pequeño/química , Vitamina E/análogos & derivados , Vitamina E/síntesis química , Animales , Sistemas de Liberación de Medicamentos/métodos , Humanos , Hígado/metabolismo , Ratones , Neomicina/química , Interferencia de ARN , ARN Bicatenario/administración & dosificación , ARN Bicatenario/química , Vitamina E/química

RESUMEN

Both multicomponent reactions and diversity oriented synthesis are indispensable tools for the modern medicinal chemist. However, their employment for the synthesis of multivalent glycomimetics has not been exploited so far although the importance that such compounds play in exploring multivalency on glycoside inhibition. Herein, we report the combinatorial synthesis of diversity oriented hetero di- and trivalent glycomimetics through a multicomponent domino process. The process is high yielding and very general, working efficiently with easily accessible sugar starting materials such as glycosylamines, glycosylazides, and glycosylisothiocyanates, having the reactive functional groups tethered either directly to the anomeric carbon, through a suitable linker, or to the primary 6 position of hexoses (or 5 position of pentoses), leading, in the latter case, to glycomimetics with artificial enzymatically stable backbone. The process has been also exploited for the multicomponent synthesis of aminoglycoside (neomycin) conjugates.

Asunto(s)

Biomimética , Glicoconjugados/síntesis química , Neomicina/análogos & derivados , Técnicas Químicas Combinatorias/métodos , Glicoconjugados/química , Espectroscopía de Resonancia Magnética , Estructura Molecular , Neomicina/síntesis química , Neomicina/química , Espectrometría de Masa por Ionización de Electrospray

RESUMEN

Fluorogenic sulforhodamine-neomycin conjugates have been designed and synthesized for RNA tagging. Conjugates were fluorescently activated by binding to RNA aptamers and exhibited greater than 250-400 fold enhancement in binding affinity relative to corresponding unconjugated fluorophores.

Asunto(s)

Aptámeros de Nucleótidos/química , Colorantes Fluorescentes/química , Neomicina/química , Rodaminas/química , Sitios de Unión , Colorantes Fluorescentes/síntesis química , Neomicina/síntesis química , Rodaminas/síntesis química

RESUMEN

Synthesis of amphiphilic oligosaccharides is problematic because traditional methods for separating and purifying oligosaccharides, including sulfated oligosaccharides, are generally not applicable to working with amphiphilic sugars. We report here RPIP-LC and LC-MS methods that enable the synthesis, separation, and characterization of amphiphilic N-arylacyl O-sulfonated aminoglycosides, which are being pursued as small-molecule glycosaminoglycan mimics. The methods described in this work for separating and characterizing these amphiphilic saccharides are further applied to a number of uses: monitoring the progression of sulfonation reactions with analytical RP-HPLC, characterizing sulfate content for individual molecules with ESI-MS, determining the degree of sulfation for products having mixed degrees of sulfation with HPLC and LC-MS, and purifying products with benchtop C18 column chromatography. We believe that the methods described here will be broadly applicable to enabling the synthesis, separation, and characterization of amphiphilic, sulfated, and phosphorylated oligosaccharides and other types of molecules substituted to varying degrees with both anionic and hydrophobic groups.

Asunto(s)

Kanamicina/análogos & derivados , Neomicina/análogos & derivados , Ésteres del Ácido Sulfúrico/síntesis química , Cromatografía Líquida de Alta Presión , Cromatografía de Fase Inversa , Kanamicina/síntesis química , Kanamicina/aislamiento & purificación , Nebramicina/análogos & derivados , Neomicina/síntesis química , Neomicina/aislamiento & purificación , Espectrometría de Masa por Ionización de Electrospray , Ésteres del Ácido Sulfúrico/química , Ésteres del Ácido Sulfúrico/aislamiento & purificación

RESUMEN

A series of neomycin dimers have been synthesized using 'click chemistry' with varying linker functionality and length to target the TAR RNA region of HIV virus. TAR (trans activation response) RNA region, a 59 base pair stem loop structure located at 5'-end of all nascent HIV-1 transcripts interacts with a key regulatory protein, Tat, and necessitates the replication of HIV-1 virus. Neomycin, an aminosugar, has been shown to exhibit more than one binding site with HIV TAR RNA. Multiple TAR binding sites of neomycin prompted us to design and synthesize a small library of neomycin dimers using click chemistry. The binding between neomycin dimers and HIV TAR RNA was characterized using spectroscopic techniques including FID (Fluorescent Intercalator Displacement) titration and UV-thermal denaturation. UV thermal denaturation studies demonstrate that neomycin dimer binding increase the melting temperature (T(m)) of the HIV TAR RNA up to 10°C. Ethidium bromide displacement titrations revealed nanomolar IC(50) between neomycin dimers and HIV TAR RNA, whereas with neomycin, a much higher IC(50) in the micromolar range is observed.

Asunto(s)

Duplicado del Terminal Largo de VIH/efectos de los fármacos , Neomicina/farmacología , ARN Viral/efectos de los fármacos , Triazoles/farmacología , Química Clic , Dimerización , Ligandos , Conformación Molecular , Neomicina/síntesis química , Neomicina/química , ARN Viral/química , Bibliotecas de Moléculas Pequeñas , Relación Estructura-Actividad , Triazoles/química

RESUMEN

A library of 5''-modified neomycin derivatives were synthesized for an antibacterial structure-activity optimization strategy. Two leads exhibited prominent activity against both methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). Antibacterial activities were measured when combined with other clinically used antibiotics. Significant synergistic activities were observed, which may lead to the development of novel therapeutic practices in the battle against infectious bacteria.

Asunto(s)

Antibacterianos , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Neomicina , Antibacterianos/síntesis química , Antibacterianos/química , Antibacterianos/farmacología , Sinergismo Farmacológico , Quimioterapia Combinada , Enterococcus/efectos de los fármacos , Humanos , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Conformación Molecular , Neomicina/análogos & derivados , Neomicina/síntesis química , Neomicina/química , Neomicina/farmacología , Relación Estructura-Actividad , Resistencia a la Vancomicina

RESUMEN

Aminoglycoside antibiotics and cationic detergents constitute two classes of clinically important drugs and antiseptics. Their bacteriological and clinical efficacy, however, has decreased recently due to antibiotic resistance. We have synthesized aminoglycoside-lipid conjugates in which the aminoglycoside neomycin forms the cationic headgroup of a polycationic detergent. Our results show that neomycin-C16 and neomycin-C20 conjugates exhibit strong Gram-positive activity but reduced Gram-negative activity. The MIC of neomycin-C16 (C20) conjugates against methicillin-resistant Staphylococcus aureus (MRSA) is comparable to clinically used antiseptics.

Asunto(s)

Antibacterianos/farmacología , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Lípidos/farmacología , Neomicina/farmacología , Poliaminas/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Bacterias Gramnegativas/crecimiento & desarrollo , Bacterias Grampositivas/crecimiento & desarrollo , Interacciones Hidrofóbicas e Hidrofílicas , Lípidos/síntesis química , Lípidos/química , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Neomicina/síntesis química , Neomicina/química , Poliaminas/síntesis química , Poliaminas/química , Polielectrolitos , Estereoisomerismo

RESUMEN

While the resistance of bacteria to traditional antibiotics is a major public health concern, the use of extremely potent antibacterial agents is limited by their lack of selectivity. As in cancer therapy, antibacterial targeted therapy could provide an opportunity to reintroduce toxic substances to the antibacterial arsenal. A desirable targeted antibacterial agent should combine binding specificity, a large drug payload per binding event, and a programmed drug release mechanism. Recently, we presented a novel application of filamentous bacteriophages as targeted drug carriers that could partially inhibit the growth of Staphylococcus aureus bacteria. This partial success was due to limitations of drug-loading capacity that resulted from the hydrophobicity of the drug. Here we present a novel drug conjugation chemistry which is based on connecting hydrophobic drugs to the phage via aminoglycoside antibiotics that serve as solubility-enhancing branched linkers. This new formulation allowed a significantly larger drug-carrying capacity of the phages, resulting in a drastic improvement in their performance as targeted drug-carrying nanoparticles. As an example for a potential systemic use for potent agents that are limited for topical use, we present antibody-targeted phage nanoparticles that carry a large payload of the hemolytic antibiotic chloramphenicol connected through the aminoglycoside neomycin. We demonstrate complete growth inhibition toward the pathogens Staphylococcus aureus, Streptococcus pyogenes, and Escherichia coli with an improvement in potency by a factor of approximately 20,000 compared to the free drug.

Asunto(s)

Antibacterianos/farmacología , Bacterias , Bacteriófagos/fisiología , Portadores de Fármacos , Sistemas de Liberación de Medicamentos , Nanopartículas , Antibacterianos/síntesis química , Antibacterianos/química , Bacterias/efectos de los fármacos , Bacterias/genética , Bacterias/crecimiento & desarrollo , Bacterias/virología , Infecciones Bacterianas/terapia , Bacteriófagos/clasificación , Cloranfenicol/síntesis química , Cloranfenicol/química , Cloranfenicol/farmacología , Portadores de Fármacos/síntesis química , Portadores de Fármacos/química , Portadores de Fármacos/metabolismo , Escherichia coli/efectos de los fármacos , Escherichia coli/genética , Escherichia coli/crecimiento & desarrollo , Escherichia coli/virología , Humanos , Nanomedicina/métodos , Neomicina/síntesis química , Neomicina/química , Neomicina/farmacología , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/genética , Staphylococcus aureus/crecimiento & desarrollo , Staphylococcus aureus/virología , Streptococcus pyogenes/efectos de los fármacos , Streptococcus pyogenes/genética , Streptococcus pyogenes/crecimiento & desarrollo , Streptococcus pyogenes/virología

RESUMEN

Facilitating the uptake of molecules into living cells is of substantial interest for basic research and drug delivery applications. Arginine-rich peptides have been shown to facilitate uptake of high molecular mass cargos into cells, but the mechanism of uptake is complex and may involve multiple receptors. In this report, we show that a derivative of the aminoglycoside antibiotic neomycin, in which all of the ammonium groups have been converted into guanidinium groups, can carry large (>300 kDa) bioactive molecules across cell membranes. Delivery occurs at nanomolar transporter concentrations and under these conditions depends entirely on cell surface heparan sulfate proteoglycans. Conjugation of guanidinoneomycin to the plant toxin saporin, a ribosome-inactivating agent, results in proteoglycan-dependent cell toxicity. In contrast, an arginine-rich peptide shows both heparan sulfate-dependent and -independent cellular uptake. The high selectivity of guanidinoneomycin for heparan sulfate suggests the possibility of exploiting differences in proteoglycan compositions to target delivery to different cell types.

Asunto(s)

Sistemas de Liberación de Medicamentos , Proteoglicanos de Heparán Sulfato/metabolismo , Glicoproteínas de Membrana/metabolismo , Neomicina/farmacocinética , Inhibidores de la Síntesis de la Proteína/farmacocinética , Animales , Transporte Biológico/efectos de los fármacos , Transporte Biológico/fisiología , Células CHO , Cricetinae , Cricetulus , Relación Dosis-Respuesta a Droga , Guanidina/análogos & derivados , Guanidina/síntesis química , Guanidina/farmacocinética , N-Glicosil Hidrolasas/farmacocinética , Neomicina/análogos & derivados , Neomicina/síntesis química , Péptidos/síntesis química , Péptidos/farmacocinética , Proteínas de Plantas/farmacocinética , Unión Proteica/efectos de los fármacos , Inhibidores de la Síntesis de la Proteína/síntesis química , Proteínas Inactivadoras de Ribosomas Tipo 1 , Saporinas

RESUMEN

The synthesis of neomycin covalently attached at the C5-position of 2'-deoxyuridine is reported. The synthesis outlined allows for incorporation of an aminoglycoside (neomycin) at any given site in an oligonucleotide (ODN) where a thymidine (or uridine) is present. Incorporation of this modified base into an oligonucleotide, which is complementary to a seven-bases-long alpha-sarcin loop RNA sequence, leads to enhanced duplex hybridization. The increase in Tm for this duplex (DeltaTm = 6 degrees C) suggests a favorable interaction of neomycin within the duplex groove. CD spectroscopy shows that the modified duplex adopts an A-type confirmation. ITC measurements indicate the additive effects of ODN and neomycin binding to the RNA target (Ka = 4.5 x 107 M-1). The enhanced stability of the hybrid duplex from this neomycin-ODN conjugate originates primarily from the enthalpic contribution of neomycin {DeltaDeltaHobs = -7.21 kcal/mol (DeltaHneomycin conjugated - DeltaH nonconjugated)} binding to the hybrid duplex. The short linker length allows for selective stabilization of the hybrid duplex over the hybrid triplex. The results described here open up new avenues in the design and synthesis of nucleo-aminoglycoside-conjugates (N-Ag-C) where the inclusion of any number of aminoglycoside (neomycin) molecules per oligonucleotide can be accomplished.

Asunto(s)

Neomicina/química , Oligonucleótidos/química , ARN/química , Secuencia de Bases , Calorimetría , Dicroismo Circular , Modelos Moleculares , Neomicina/síntesis química , Nitrógeno/química , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Termodinámica , Volumetría , Temperatura de Transición

RESUMEN

Recent developments have indicated that aminoglycoside binding is limited not to RNA but to nucleic acids that, like RNA, adopt conformations similar to the A-form. We have further sought to expand the utility of aminoglycoside binding to B-DNA structures by conjugating neomycin, an aminoglycoside antibiotic, with the B-DNA minor groove binding ligand Hoechst 33258. Described herein are novel neomycin-Hoechst 33258 conjugates developed for exploring B-DNA groove recognition. We have varied the two reported conjugates in linker length and composition in an effort to improve our understanding of the spatial differences that define B-DNA binding. Spectroscopic studies such as ultraviolet (UV) melting, isothermal fluorescence titrations, differential scanning calorimetry (DSC), and circular dichroism (CD) together illustrate the mode of binding by such conjugates. Both conjugates exhibit enhanced thermal stabilization of A.T rich duplexes when compared to Hoechst 33258.

Asunto(s)

Secuencia Rica en At , Bencimidazoles/química , ADN/química , Neomicina/química , Conformación de Ácido Nucleico , Bencimidazoles/síntesis química , Dicroismo Circular , Neomicina/síntesis química , Conformación de Ácido Nucleico/efectos de la radiación , ARN/química , Espectrofotometría Ultravioleta , Rayos Ultravioleta

RESUMEN

[reaction: see text] A novel method for achieving the desired regioselective reduction of the N-1 azido group on a tetraazidoneamine has been developed that leads to the synthesis of both kanamycin and neomycin class antibiotics bearing N-1 modification. Both classes of aminoglycosides are active against aminoglycoside-resistant bacteria carrying APH(3')-I and AAC(6')/APH(2'').

Asunto(s)

Antibacterianos/síntesis química , Escherichia coli/efectos de los fármacos , Kanamicina/síntesis química , Neomicina/síntesis química , Amicacina/farmacología , Antibacterianos/química , Antibacterianos/clasificación , Farmacorresistencia Microbiana , Kanamicina/análogos & derivados , Kanamicina/química , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Neomicina/química , Estereoisomerismo , Relación Estructura-Actividad

RESUMEN

Synthesis of a neomycin-Hoechst 33258 conjugate is reported. The conjugate combines the ligands known to selectively bind in the duplex and the triplex groove. The conjugate stabilizes DNA duplex over DNA triplex. The conjugate selectively stabilizes the DNA duplex (in the presence of salt), with as little as 2 muM of the ligand leading to a DeltaTm of 25 degrees C.

Asunto(s)

Bisbenzimidazol/análogos & derivados , ADN/metabolismo , Neomicina/análogos & derivados , Bisbenzimidazol/síntesis química , Bisbenzimidazol/metabolismo , ADN/química , Modelos Moleculares , Neomicina/síntesis química , Neomicina/metabolismo , Conformación de Ácido Nucleico

RESUMEN

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.

Asunto(s)

Antibacterianos/síntesis química , Antibacterianos/farmacología , Neomicina/síntesis química , Neomicina/farmacología , ARN Ribosómico/metabolismo , Antibacterianos/química , Sitios de Unión , Isomerismo , Neomicina/química , Biosíntesis de Proteínas/efectos de los fármacos , ARN Ribosómico/antagonistas & inhibidores

RESUMEN

As mimetics of neamine, several 4-heterocyclic 2-deoxystreptamine derivatives were chemically synthesized for RNA recognition. Conversion of 4-methylthiomethyl-5,6-di-O-acetyl-diazido-2-deoxystreptamine to the 4-chloromethyl derivative followed by reactions with different nuclophilic reagents gave the 4-heterocyclic 2-deoxystreptamine derivatives in satisfactory yields.

Asunto(s)

Compuestos Heterocíclicos/síntesis química , Imitación Molecular , Neomicina/síntesis química , ARN/efectos de los fármacos , Indicadores y Reactivos , Solventes

RESUMEN

The interactions of a number of aminoglycoside antibiotics with tRNA and DNA were studied by an HPLC method. based on tRNA and DNA peak size exclusion. Among the compounds studied (deoxystreptamine, neamine, neomycin B, kanamycin A, gentamicin A, netilmicin, streptomycin, and the synthetic neamine analogue BKN3), neomycin B and the synthetic analogue of neamine were proved to be the most potent binders.

Asunto(s)

Antibacterianos/metabolismo , ADN/metabolismo , Framicetina/metabolismo , Neomicina/metabolismo , ARN de Transferencia/metabolismo , Antibacterianos/química , Sitios de Unión/fisiología , Cromatografía Líquida de Alta Presión , ADN/química , Framicetina/química , Kanamicina/química , Kanamicina/metabolismo , Neomicina/análogos & derivados , Neomicina/síntesis química , Netilmicina/química , Netilmicina/metabolismo , ARN de Transferencia/química

RESUMEN

The neomycin-furazolidone-xanthan complex has been synthesized. Neomycin is covalently linked to xanthan, while furazolidone is inserted in the hydrogel formed by the reaction between neomycin and xanthan. The content of neomycin and furazolidone depends on the drug rate in the reaction medium. Thus, a zero-order kinetics is obtained for the release of both neomycin and furazolidone in basic medium. The complex's antimicrobial activity is intensified.

Asunto(s)

Sistemas de Liberación de Medicamentos , Furazolidona/administración & dosificación , Neomicina/administración & dosificación , Polisacáridos Bacterianos , Preparaciones de Acción Retardada , Portadores de Fármacos , Furazolidona/síntesis química , Furazolidona/química , Furazolidona/farmacología , Geles , Concentración de Iones de Hidrógeno , Neomicina/síntesis química , Neomicina/química , Neomicina/farmacología , Polisacáridos Bacterianos/química , Soluciones , Staphylococcus aureus/efectos de los fármacos , Factores de Tiempo

RESUMEN

trans-4-Aminocyclohexanol-2'-amino-alpha-D-glucopyranosides were prepared which are derivatives of neamine having the 3-amino and 5 and 6 hydroxyl groups of the 2-deoxystreptamine ring replaced with hydrogen. The 2'-amino-alpha-glycosides were synthesized by the method of LEMIEUX using a chloro nitroso dimer of a glucal and appropriately substituted cyclohexanols. Reductive deblocking of the intermediate 2-oximino derivatives afforded paromamine and neamine analogues. Two examples of 2'-amino-alpha-glycosides with ring-opened variations of the 2-deoxystreptamine aglycone are described. None of the compounds exhibited better in vitro antibacterial activity than neamine when compared against Gram-positive and Gram-negative bacteria.

Asunto(s)

Neomicina/análogos & derivados , Bacterias/efectos de los fármacos , Farmacorresistencia Microbiana , Neomicina/síntesis química , Relación Estructura-Actividad