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 VancomicinaRESUMEN
A facile synthetic protocol for the production of neomycin B derivatives with various modifications at the 5'' position has been developed. The structural activity relationship (SAR) against aminoglycoside resistant bacteria equipped with various aminoglycoside-modifying enzymes (AMEs) was investigated. Enzymatic and molecular modeling studies reveal that the superb substrate promiscuity of AMEs allows the resistant bacteria to cope with diverse structural modifications despite the observation that several derivatives show enhanced antibacterial activity compared to the parent neomycin. Surprisingly, when testing synthetic neomycin derivatives against other human pathogens, two leads exhibit prominent activity against both methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) that are known to exert a high level of resistance against clinically used aminoglycosides. These findings can be extremely useful in developing new aminoglycoside antibiotics against resistant bacteria. Our result also suggests that new biological and antimicrobial activities can be obtained by chemical modifications of old drugs.
Asunto(s)
Antibacterianos/farmacología , Enterococcus/efectos de los fármacos , Framicetina/análogos & derivados , Framicetina/farmacología , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Antibacterianos/síntesis química , Antibacterianos/química , Sitios de Unión/efectos de los fármacos , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Framicetina/química , Kanamicina Quinasa/antagonistas & inhibidores , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Estereoisomerismo , Relación Estructura-Actividad , Resistencia a la Vancomicina/efectos de los fármacosRESUMEN
[reaction: see text] The expedient synthesis of a library of kanamycin B analogues is reported. The revealed SAR will guide future designs in developing kanamycin-type aminoglycoside antibiotics against drug-resistant bacteria.
