Combination of Repurposed Drug Diosmin with Amoxicillin-Clavulanic acid Causes Synergistic Inhibition of Mycobacterial Growth

Abstract

Effective therapeutic regimens for the treatment of tuberculosis (TB) are limited. They are comprised of multiple drugs that inhibit the essential cellular pathways in Mycobacterium tuberculosis ( Mtb ). The present study investigates an approach which enables a combination of Amoxicillin-Clavulanic acid (AMC) and a repurposed drug for its synergistic effect towards TB treatment. We identified Diosmin (DIO), by targeting the active site residues of L,D-transpeptidase (Ldt) enzymes involved in Mtb cell wall biosynthesis by using a structure-based drug design method. DIO is rapidly converted into aglycone form Diosmetin (DMT) after oral administration. Binding of DIO or DMT towards Ldt enzymes was studied using molecular docking and bioassay techniques. Combination of DIO (or DMT) and AMC exhibited higher mycobactericidal activity against Mycobacterium marinum as compared to individual drugs. Scanning electron microscopy study of M. marinum treated with AMC-DIO and AMC-DMT showed marked cellular leakage. M. marinum infected Drosophila melanogaster fly model showed an increased fly survival of ~60% upon treatment with a combination of AMC and DIO (or DMT). Finally, the enhanced in vitro antimicrobial activity of AMC-DIO was validated against Mtb H37Ra and a MDR clinical isolate. Our results demonstrate the potential for AMC and DIO (or DMT) as a synergistic combination for the treatment of TB.

Flavonoids as Potential anti-MRSA Agents through Modulation of PBP2a: A Computational and Experimental Study

“…Further docking and molecular dynamic investigation not only confirmed the primary inverse virtual screening predictions but also revealed that some inactive derivatives can possibly modify the PBP2a allosteric site and hence, serve as adjuvants to reverse MRSA resistance toward β-lactams antibiotics (e.g., ampicillin 23). These findings were also in great accordance with the previous studies that highlighted polyhydroxylated flavonoids as promising synergistic agents to β-lactams antibiotics [16,21,23].…”

The Chemopreventive Potential of Diosmin and Hesperidin for COVID-19 and Its Comorbid Diseases

“…Moreover, we also realized that hesperidin and diosmin performed better binding interaction to the HR2 binding domain of S2 (S2 sub unit: 6LXT) ( Figure 4B) compared to other tested compounds. Pushkaran, et. al., 2019 Anticancer Inhibits the proliferation of MCF 7 GFP Tubulin cells and LNCaP cells.…”

A phytochemical-based medication search for the SARS-CoV-2 infection by molecular docking models towards spike glycoproteins and main proteases

“…39 The docking protocol using the GLIDE module has been successfully implemented in our previous studies. [40][41][42][43] The bioactive phytochemicals from different medicinal plants were ranked based on their docking score (or binding affinity) against the SARS-CoV-2 protein targets. The best phytochemicals were further analyzed using the PyMol and Discovery Studio visualizer to understand its molecular mechanism of action for SARS-CoV-2 infections.…”