RESUMEN
Spread of antimicrobial resistance and shortage of novel antibiotics have led to an urgent need for new antibacterials. Although aminoglycoside antibiotics (AGs) are very potent anti-infectives, their use is largely restricted due to serious side-effects, mainly nephrotoxicity and ototoxicity. We evaluated the ototoxicity of various AGs selected from a larger set of AGs on the basis of their strong antibacterial activities against multidrug-resistant clinical isolates of the ESKAPE panel: gentamicin, gentamicin C1a, apramycin, paromomycin and neomycin. Following local round window application, dose-dependent effects of AGs on outer hair cell survival and compound action potentials showed gentamicin C1a and apramycin as the least toxic. Strikingly, although no changes were observed in compound action potential thresholds and outer hair cell survival following treatment with low concentrations of neomycin, gentamicin and paromomycin, the number of inner hair cell synaptic ribbons and the compound action potential amplitudes were reduced. This indication of hidden hearing loss was not observed with gentamicin C1a or apramycin at such concentrations. These findings identify the inner hair cells as the most vulnerable element to AG treatment, indicating that gentamicin C1a and apramycin are promising bases for the development of clinically useful antibiotics.
Asunto(s)
Antibacterianos/efectos adversos , Gentamicinas/farmacología , Pérdida Auditiva/genética , Nebramicina/análogos & derivados , Ototoxicidad/metabolismo , Aminoglicósidos/efectos adversos , Aminoglicósidos/farmacología , Animales , Antiinfecciosos/efectos adversos , Antiinfecciosos/farmacología , Línea Celular , Farmacorresistencia Bacteriana/efectos de los fármacos , Farmacorresistencia Bacteriana/genética , Gentamicinas/efectos adversos , Gentamicinas/uso terapéutico , Cobayas , Células Ciliadas Auditivas Internas/efectos de los fármacos , Células Ciliadas Auditivas Internas/patología , Pérdida Auditiva/inducido químicamente , Pérdida Auditiva/patología , Humanos , Nebramicina/efectos adversos , Nebramicina/farmacología , Neomicina/efectos adversos , Neomicina/farmacología , Ototoxicidad/patología , Inhibidores de la Síntesis de la Proteína/efectos adversos , Inhibidores de la Síntesis de la Proteína/farmacología , Ventana Redonda/efectos de los fármacos , Ventana Redonda/patologíaRESUMEN
Coenzyme A is an essential metabolite known for its central role in over one hundred cellular metabolic reactions. In cells, Coenzyme A is synthesized de novo in five enzymatic steps with vitamin B5 as the starting metabolite, phosphorylated by pantothenate kinase. Mutations in the pantothenate kinase 2 gene cause a severe form of neurodegeneration for which no treatment is available. One therapeutic strategy is to generate Coenzyme A precursors downstream of the defective step in the pathway. Here we describe the synthesis, characteristics and in vivo rescue potential of the acetyl-Coenzyme A precursor S-acetyl-4'-phosphopantetheine as a possible treatment for neurodegeneration associated with pantothenate kinase deficiency.
Asunto(s)
Trastornos Heredodegenerativos del Sistema Nervioso/tratamiento farmacológico , Panteteína/análogos & derivados , Fosfotransferasas (Aceptor de Grupo Alcohol)/deficiencia , Suero/química , Animales , Línea Celular , Modelos Animales de Enfermedad , Drosophila , Humanos , Ratones , Panteteína/administración & dosificación , Panteteína/síntesis química , Panteteína/aislamiento & purificación , Panteteína/farmacocinética , Resultado del TratamientoRESUMEN
Methylnitrocatechols (MNCs) are secondary organic aerosol (SOA) tracers and major contributors to atmospheric brown carbon; however, their formation and aging processes in atmospheric waters are unknown. To investigate the importance of aqueous-phase electrophilic substitution of 3-methylcatechol with nitronium ion (NO2(+)), we performed quantum calculations of their favorable pathways. The calculations predicted the formation of 3-methyl-5-nitrocatechol (3M5NC), 3-methyl-4-nitrocatechol (3M4NC), and a negligible amount of 3-methyl-6-nitrocatechol (3M6NC). MNCs in atmospheric PM2 samples were further inspected by LC/(-)ESI-MS/MS using commercial as well as de novo synthesized authentic standards. We detected 3M5NC and, for the first time, 3M4NC. In contrast to previous reports, 3M6NC was not observed. Agreement between calculated and observed 3M5NC/3M4NC ratios cannot unambiguously confirm the electrophilic mechanism as the exclusive formation pathway of MNCs in aerosol water. However, the examined nitration by NO2(+) is supported by (1) the absence of 3M6NC in the ambient aerosols analyzed and (2) the constant 3M5NC/3M4NC ratio in field aerosol samples, which indicates their common formation pathway. The magnitude of error one could make by incorrectly identifying 3M4NC as 3M6NC in ambient aerosols was also assessed, suggesting the importance of evaluating the literature regarding MNCs with special care.
Asunto(s)
Aerosoles , Espectrometría de Masas en Tándem , Cromatografía Liquida , Compuestos Orgánicos , AguaRESUMEN
The discovery of a concise regiodivergent asymmetric route to nonclassical P-stereogenic 5- or 6-membered benzophosphacycles, under conditions-dependent radical (oxidative addition) versus anionic (S(N)Ar) benzannulation, is reported.
Asunto(s)
Compuestos Organofosforados/química , Fosfinas/química , Modelos Moleculares , Estructura Molecular , Compuestos Organofosforados/síntesis química , EstereoisomerismoRESUMEN
Temporary silicon-tethered ring-closing metathesis represents an important cross-coupling strategy for the formation of medium-sized silacycles. These intermediates are valuable synthons in organic synthesis due to their propensity to undergo a facile refunctionalization through protodesilylation, oxidation, silane-group transfer or transmetallation. A particularly attractive utility of this methodology is an application in the synthesis of biologically important natural products. The purpose of this review article is to highlight the recent progress in methodology development and its strategic application toward the target-directed synthesis.
Asunto(s)
Alquenos/química , Productos Biológicos/síntesis química , Compuestos de Organosilicio/química , Silanos/síntesis química , Productos Biológicos/química , Técnicas de Química Analítica , Estructura Molecular , Silanos/química , EstereoisomerismoRESUMEN
RATIONALE: Studying the chemical composition of biomass burning aerosol (BBA) is very important in order to assess their impact on the climate and the biosphere. In the present study, we focus on the characterization of some newly recognized biomass burning aerosol tracers including methyl nitrocatechols, nitroguaiacols and 4-nitrocatechol, but also on nitrophenols, methyl nitrophenols and nitrosalicylic acids, using liquid chromatography tandem mass spectrometry. METHODS: For the purpose of their separation and detection in atmospheric aerosol, a new chromatographic method was initially developed based on reversed-phase chromatography coupled with ultraviolet/visible (UV/Vis) detection. The method was afterwards transferred to a liquid chromatography/electrospray ionization linear ion trap mass spectrometry (LC/ESI-LITMS) system in order to identify the targeted analytes in winter aerosol from the city of Maribor, Slovenia, using their chromatographic retention times and characteristic (-)ESI product ion (MS(2) ) spectra. RESULTS: The fragmentation patterns of analytes obtained with LITMS are presented. Additional nitro-aromatic compounds (m/z 168 and 182) closely related to the targeted nitrocatechols and nitroguaiacols were detected in the aerosol. According to their MS(2) spectra these compounds could be attributed to methyl homologues of methyl nitrocatechols and nitroguaiacols. CONCLUSIONS: The proposed LC/MS method results in a better separation and specificity for the targeted analytes. Several nitro-aromatic compounds were detected in urban BBA. The LC/MS peak intensity of the newly detected methyl nitrocatechols and nitroguaiacols is comparable to that of the methyl nitrocatechols, which also qualifies them as suitable molecular tracers for secondary biomass burning aerosol.