The rise of β-Lactamase mediated antibiotic resistance is a major concern for public health; hence, there is an urgent need to find new treatment approaches. Structure-guided drug repurposing offers a promising approach to swiftly deliver essential therapeutics in the fight against escalating antibiotic resistance. Here, a structure-guided virtual screening approach was used involving drug profiling, molecular docking, and molecular dynamics (MD) simulation to identify existing drugs against β-Lactamase-associated drug resistance. We exploited a large panel of FDA-approved drugs to an extensive in silico analysis to ascertain their ability to inhibit β-Lactamase. First, molecular docking investigations were performed to assess the binding affinities and interactions of screened molecules with the active site of β-Lactamase enzymes. Out of all the screened candidates, Aristospan was identified to possess promising characteristics, which include appropriate drug profiles, high binding specificity, and efficiency towards the binding pocket of β-Lactamase. Further analysis showed that Aristospan possesses several desirable biological characteristics and tends to bind to the β-Lactamase binding site. To explore the interactions further, the best docking pose of Aristospan was selected for MD simulations to assess the thermodynamic stability of the drug-enzyme complex and its conformational changes over 500 ns. The MD simulations in independent replica runs demonstrated that the β-Lactamase-Aristospan complex was stable in the 500 ns trajectory. These enlightening results suggest that Aristospan may harbor the potential for further evolution into a possible β-Lactamase inhibitor, with potential applications in overcoming antibiotic resistance in both Gram-positive and Gram-negative bacteria.

We selected fifty one drugs already known for their potential disease treatment roles in various studies and subjected to docking and molecular docking simulation (MDS) analyses. Five of them showed promising features that are discussed and suggested as potential candidates for repurposing for COVID-19. These top five compounds were boswellic acid, pimecrolimus, GYY-4137, BMS-345541 and triamcinolone hexacetonide that interacted with the chosen receptors 1R42, 4G3D, 6VW1, 6VXX and 7MEQ, respectively with binding energies of -9.2 kcal/mol, -9.1 kcal/mol, -10.3 kcal/mol, -10.1 kcal/mol and -8.7 kcal/mol, respectively. The MDS studies for the top 5 best complexes revealed binding features for the chosen receptor, human NF-kappa B transcription factor as an important drug target in COVID-19-based drug development strategies.

Patients with knee osteoarthritis often receive glucocorticoid (GC) or hyaluronic acid (HA) injections to alleviate symptoms. This study evaluated the impact of Triamcinolone Hexacetonide (a GC), HA, and a combination of both on bovine osteochondral grafts exposed to IL-1β and IL-17 in an ex vivo culture. Metabolic activity increased with GC treatment. GCs and GCs/HA counteracted cytokine effects, with gene expressions similar to untreated controls, while HA alone did not. However, HA improved the coefficient of friction after two weeks. The highest friction values were observed in GC-containing and cytokine-treated groups. Cytokine treatment reduced tissue proteoglycan content, which HA could mitigate, especially in the GC/HA combination. This combo also effectively controlled proteoglycan release, supported by reduced sGAG release. Cytokine treatment led to surface cell death, while GCs, HA, or their combination showed protective effects against inflammation. The GC/HA combination had the best overall results, suggesting its potential as a superior treatment option for osteoarthritis.

Advanced drug delivery strategies can be used to enhance the therapeutic effectiveness of locally delivered corticosteroids. Poly(δ-valerolactone-co-allyl-δ-valerolactone) microparticles (PVL-co-PAVL MPs) were evaluated for delivery of two corticosteroids, triamcinolone acetonide and triamcinolone hexacetonide. PVL-co-PAVL MPs were prepared using a modified oil-in-water emulsification method, followed by a UV-initiated cross-linking process. The resulting PVL-co-PAVL MPs were purified with an excess amount of water and then acetone to remove residual surfactant, cross-linker, and catalyst before lyophilization. Triamcinolone acetonide and triamcinolone hexacetonide were independently loaded into the resulting PVL-co-PAVL MPs via a post-loading swelling-equilibrium method. The drug-loaded MPs were characterized in terms of drug loading (determined by high-performance liquid chromatography, HPLC), thermal properties (determined by differential scanning calorimetry, DSC), and in vitro drug release kinetics (with quantification of drug using HPLC) to better understand the suitability of PVL-co-PAVL MPs for delivery of corticosteroids. These data demonstrate the potential of PVL-co-PAVL MPs as a promising drug delivery platform for the sustained release of corticosteroids. Raw data have been made available on Mendeley Data. Additional details on PVL-co-PAVL MPs were previously reported [1].

[This retracts the article DOI: 10.3389/fvets.2020.609889.].