RESUMEN
Aminoglycoside antibiotics are pseudosaccharides decorated with ammonium groups that are critical for their potent broad-spectrum antibacterial activity. Despite over three decades of speculation whether or not modulation of pKa is a viable strategy to curtail aminoglycoside kidney toxicity, there is a lack of methods to systematically probe amine-RNA interactions and resultant cytotoxicity trends. This study reports the first series of potent aminoglycoside antibiotics harboring fluorinated N1-hydroxyaminobutyryl acyl (HABA) appendages for which fluorine-RNA contacts are revealed through an X-ray cocrystal structure within the RNA A-site. Cytotoxicity in kidney-derived cells was significantly reduced for the derivative featuring our novel ß,ß-difluoro-HABA group, which masks one net charge by lowering the pKa without compromising antibacterial potency. This novel side-chain assists in evasion of aminoglycoside-modifying enzymes, and it can be easily transferred to impart these properties onto any number of novel analogs.
Asunto(s)
Aminoglicósidos/química , Aminoglicósidos/farmacología , Antibacterianos/química , Antibacterianos/farmacología , Neomicina/análogos & derivados , Aminoglicósidos/toxicidad , Antibacterianos/síntesis química , Antibacterianos/toxicidad , Línea Celular/efectos de los fármacos , Técnicas de Química Sintética , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos/métodos , Farmacorresistencia Bacteriana/efectos de los fármacos , Humanos , Riñón/citología , Riñón/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , ARN/química , ARN/metabolismo , Relación Estructura-ActividadRESUMEN
Biosynthetically inspired manipulation of the antibiotic paromomycin led, in six high-yielding steps, to a ring A harboring an α,ß-unsaturated 6'-aldehyde and an allylic 3'-methylcarbonate group. Tsuji deoxygenation in the presence of 5 mol % Pd(2)(dba)(3) and Bu(3)P granted access to a novel series of 3',4'-dideoxy-4',5'-dehydro ring A hybrids. The neomycin-sisomicin hybrid exhibited superior in vitro antibacterial activity to the parent compound neomycin.
Asunto(s)
Aminoglicósidos/síntesis química , Antibacterianos/síntesis química , Paladio/química , Aminoglicósidos/química , Antibacterianos/química , Catálisis , Neomicina/química , Oxidación-Reducción , Paromomicina/química , Sisomicina/químicaRESUMEN
Deoxygenation of the diol groups in rings A and D of neomycin in combination with the introduction of an N1-(l)-HABA group in the 2-deoxystreptamine subunit (ring B) leads to a novel and potent antibiotic (1) with activity against strains of S. aureus carrying known aminoglycoside resistance determinants, as well as against an extended panel of Methicillin-resistant S. aureus isolates (n = 50). Antibiotic 1 displayed >64 fold improvement in MIC50 and MIC90 against this MRSA collection when compared to the clinically relevant aminoglycosides amikacin and gentamicin. The synthesis was achieved in six steps and 15% overall yield.
RESUMEN
ACHN-490 is a neoglycoside, or "next-generation" aminoglycoside (AG), that has been identified as a potentially useful agent to combat drug-resistant bacteria emerging in hospitals and health care facilities around the world. A focused medicinal chemistry campaign produced a collection of over 400 sisomicin analogs from which ACHN-490 was selected. We tested ACHN-490 against two panels of Gram-negative and Gram-positive pathogens, many of which harbored AG resistance mechanisms. Unlike legacy AGs, ACHN-490 was active against strains expressing known AG-modifying enzymes, including the three most common such enzymes found in Enterobacteriaceae. ACHN-490 inhibited the growth of AG-resistant Enterobacteriaceae (MIC(90), ≤4 µg/ml), with the exception of Proteus mirabilis and indole-positive Proteae (MIC(90), 8 µg/ml and 16 µg/ml, respectively). ACHN-490 was more active alone in vitro against Pseudomonas aeruginosa and Acinetobacter baumannii isolates with AG-modifying enzymes than against those with altered permeability/efflux. The MIC(90) of ACHN-490 against AG-resistant staphylococci was 2 µg/ml. Due to its promising in vitro and in vivo profiles, ACHN-490 has been advanced into clinical development as a new antibacterial agent.
Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/farmacología , Sisomicina/análogos & derivados , Acinetobacter baumannii/efectos de los fármacos , Antibacterianos/química , Enterobacteriaceae/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Proteus mirabilis/efectos de los fármacos , Pseudomonas aeruginosa/efectos de los fármacos , Sisomicina/síntesis química , Sisomicina/química , Sisomicina/farmacologíaRESUMEN
We determined the in vitro MIC of arbekacin against 200 Acinetobacter isolates recovered from wounded soldiers. The median MIC was 2 microg/ml (range, 0.5 to > 64 microg/ml). A total of 97.5% of the isolates had arbekacin MICs of < 8 microg/ml and 86.5% had MICs of < or = 4 microg/ml. There was no association between the arbekacin MIC and susceptibility to 16 other antibiotics or the specimen source (P = 0.7239). Synergy testing suggested an enhanced effect of arbekacin-carbapenem combinations.
Asunto(s)
Acinetobacter baumannii/efectos de los fármacos , Aminoglicósidos/farmacología , Antibacterianos/farmacología , Hospitales Militares , Acinetobacter baumannii/aislamiento & purificación , Carbapenémicos/farmacología , Dibekacina/análogos & derivados , Dibekacina/farmacología , Humanos , Pruebas de Sensibilidad Microbiana , GuerraRESUMEN
Respiratory syncytial virus (RSV)-induced chemokine gene expression occurs through the activation of a subset of transcription factors, including Interferon Regulatory Factor (IRF)-3. In this study, we have investigated the signaling pathway leading to RSV-induced IRF-3 activation and whether it is mediated by intracellular reactive oxygen species (ROS) generation. Our results show that RSV infection induces expression and catalytic activity of IKKepsilon, a noncanonical IKK-like kinase. Expression of a kinase-inactive IKKepsilon blocks RSV-induced IRF-3 serine phosphorylation, nuclear translocation and DNA-binding, leading to inhibition of RANTES gene transcription, mRNA expression and protein synthesis. Treatment of alveolar epithelial cells with antioxidants or with NAD(P)H oxidase inhibitors abrogates RSV-induced chemokine secretion, IRF-3 phosphorylation and IKKepsilon induction, indicating that ROS generation plays a fundamental role in the signaling pathway leading to IRF-3 activation, therefore, identifying a novel molecular target for the development of strategies aimed to modify the inflammatory response associated with RSV infection of the lung.