RESUMO
Photodynamic inhibition (PDI) of bacteria represents a powerful strategy for dealing with multidrug-resistant pathogens and infections, as it exhibits minimal development of antibiotic resistance. The PDI action stems from the generation of a triplet state in the photosensitizer (PS), which subsequently transfers energy or electrons to molecular oxygen, resulting in the formation of reactive oxygen species (ROS). These ROS are then able to damage cells, eventually causing bacterial eradication. Enhancing the efficacy of PDI includes the introduction of heavy atoms to augment triplet generation in the PS, as well as membrane intercalation to circumvent the problem of the short lifetime of ROS. However, the former approach can pose safety and environmental concerns, while achieving stable membrane partitioning remains challenging due to the complex outer envelope of bacteria. Here, we introduce a novel PS, consisting of a metal-free donor-acceptor thiophene-based conjugate molecule (BV-1). It presents several advantageous features for achieving effective PDI, namely: (i) it exhibits strong light absorption due to the conjugated donor-acceptor moieties; (ii) it exhibits spontaneous and stable membrane partitioning thanks to its amphiphilicity, accompanied by a strong fluorescence turn-on; (iii) it undergoes metal-free intersystem crossing, which occurs preferentially when the molecule resides in the membrane. All these properties, which we rationalized via optical spectroscopies and calculations, enable the effective eradication of Escherichia coli, with an inhibition concentration that is below that of current state-of-the-art treatments. Our approach holds significant potential for the development of new PS for controlling bacterial infections, particularly those caused by Gram-negative bacteria.
RESUMO
The Suzuki-Miyaura reaction between the aryl halide (1) and the phenyl boronic acid (2), in the presence of the palladium(0) complex (3) as catalyst, gives the cross-coupling product (4) in quantitative yield when performed in basic aqueous solution of the nonionic surfactant Kolliphor-EL (K-EL). The partition between the aqueous and micellar environments of the species of this reaction has been investigated by means of Molecular Dynamics (MD) simulations. Starting from the K-EL molecules dispersed in water, a micelle model has been generated by MD simulations, adopting the 2016H66 force field. Reagent and product species have been described with the same force field, once the reliability of this force field has been tested comparing the n-octanol/water partition free energies calculated from the MD and Free Energy Perturbation (FEP) method with those obtained from the quantum-mechanical SMD method. The potential of mean force for the transfer process between water and the micellar phase of the different species has been calculated by the MD simulations and the Umbrella Sampling (US) method. The overall picture that emerges from these results confirms that the molecular species involved in this reaction prefers the micellar environment and concentrates in different but close zones of the micelle. This supports the experimental evidence that the use of suitable surfactant agents promotes reactivity, allowing micelles to behave as nanoreactors in which reactive species are solubilized and enhance their local concentration.
