RESUMEN
The achievement of smart pharmaceuticals whose bioactivity can be spatiotemporally controlled by light stimuli is known as photopharmacology, an emerging area aimed at improving the therapeutic outcome and minimizing side effects. This is especially attractive for antibiotics, for which the inevitable development of multidrug resistance and the dwindling of new clinically approved drugs represent the main drawbacks. Here, we show that nitrosation of the fluoroquinolone norfloxacin (NF), a broad-spectrum antibiotic, leads to the nitrosated bioconjugate NF-NO, which is inactive at the typical minimum inhibitory concentration of NF. Irradiation of NF-NO with visible blue light triggers the simultaneous release of NF and nitric oxide (NO). The photouncaging process is accompanied by the revival of the typical fluorescence emission of NF, quenched in NF-NO, which acts as an optical reporter. This permits the real-time monitoring of the photouncaging process, even within bacteria cells where antibacterial activity is switched on exclusively upon light irradiation. The mechanism of photorelease seems to occur through a two-step hopping electron transfer mediated by the lowest triplet state of NF-NO and the phosphate buffer ions or aminoacids such as tyrosine. Considering the well-known role of NO as an "unconventional" antibacterial, the NF-NO conjugate may represent a potential bimodal antibacterial weapon activatable on demand with high spatio-temporal control.
RESUMEN
A hydrophobic nitric oxide (NO) photodonor integrating both nitroso and nitro functionalities within its chromophoric skeleton has been synthesized. Excitation of this compound with blue light triggers the release of two NO molecules from the nitroso and the nitro functionalities via a stepwise mechanism. Encapsulation of the NO photodonor within biocompatible neutral, cationic, and anionic ß-cyclodextrin branched polymers as suitable carriers leads to supramolecular nanoassemblies, which exhibit the same nature of the photochemical processes but NO photorelease performances enhanced by about 1 order of magnitude when compared with the free guest. Antibacterial tests carried out with methicillin-resistant Staphylococcus aureus and Acinetobacter baumannii demonstrate an effective antibacterial activity exclusively under light activation and point out a differentiated role of the polymeric nanocarriers in determining the outcome of the antibacterial photodynamic action.
RESUMEN
Developing biocompatible nitric oxide (NO) photoreleasing nanoconstucts is of great interest in view of the large variety of biological roles that NO plays and the unique advantage light offers in controlling NO release in space and time. In this contribution, we report the supramolecular assemblies of two NO photodonors (NOPDs), NBF-NO and RHD-NO, as water-dispersible nanogels, ca. 10 nm in diameter, based on γ-cyclodextrins (γ-CDng). These NOPDs, containing amino-nitro-benzofurazan and rhodamine chromophores as light harvesting antennae, can be activated by visible light, are highly hydrophobic and can be effectively entrapped within the γ-CDng. Despite being confined in a very restricted environment, neither NOPD suffer self-aggregation and preserve their photochemical and photophysical properties well. The blue light excitation of the weakly fluorescent γ-CDng/NBF-NO complex results in effective NO release and the concomitant generation of the highly green, fluorescent co-product, which acts as an optical NO reporter. Moreover, the green light excitation of the persistent red fluorescent γ-CDng/RHD-NO triggers NO photorelease without significantly modifying the emission properties. The activatable and persistent fluorescence emissions of the NOPDs are useful for monitoring their interactions with the Gram-positive methicillin-resistant Staphylococcus aureus, whose growth is significantly inhibited by γ-CDng/RHD-NO upon green light irradiation.