Antimicrobial agents were considered “Super Drugs” when first discovered in the 20th century. Since then, antibiotics have been used as first-line treatments for many bacterial infections. However, over the years, bacteria have developed resistance, thereby making treatment of antibiotic-resistant bacterial infections difficult. DNA gyrase is a type IIA topoisomerase which catalyzes changes in DNA during replication by introducing negative supercoils and, hence, is a well-validated drug target for antibacterial drug discovery. Currently, fluoroquinolone and aminocoumarin classes of antibiotics act by inhibiting bacterial DNA gyrase. Although, fluoroquinolones are used for gram-negative bacterial infections and have limited activity against gram-positive bacteria. Similarly, novobiocin, an aminocoumarin class of antibiotics, was initially clinically approved but was later withdrawn from the market due to safety issues and poor pharmacological properties. Computer-aided drug design has emerged as an important tool for drug discovery within the last decade. Therefore, in the proposed work, we utilised a docking-based virtual screening (DBVS) approach to identify novel DNA gyrase inhibitors. In this study, a database containing seven million molecules were subjected to an in silico DBVS workflow against DNA gyrase. Thirty-eight molecules were selected and evaluated for their antimicrobial activity. Four non-fluoroquinolone class of compounds were identified and produced minimum inhibitory concentration values of 0.5-8 µg/mL against 12 strains of bacteria. Future work will see all four lead compounds tested for their DNA gyrase inhibitory potential and used as a basis for the development of novel DNA gyrase targeted antibiotics.

Discovery of novel antimicrobial compounds using structure-based virtual screening

ACS Spring Meeting 2021

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