Docking of novel flavonoids with beta-ketoacyl acyl carrier protein synthases of Staphylococcus aureus and Escheria coli.

Abstract

The emergence of antibiotic-resistant bacteria is increasing rapidly across the globe. With more bacterial strains expressing resistance to antibiotics, there is an urgent need to obtain new methods of treating these bacterial infections. A promising target for developing alternate therapeutic agents is the inhibition of fatty acid synthesis, particularly targeting the beta-ketoacyl acyl carrier protein synthases, KAS I, II, and III. Flavonoids are compounds extracted from plants that have been reported to be successful inhibitors of KAS I and III in E. coli as well as KAS III in S. aureus. Flavonoids that have distinct 4'-OH and 7-OH positioned substituents were reported to display the greatest antimicrobial activity against various MRSA strains in in vitro studies. This study used AutoDock Vina to perform docking studies, analyzing the binding affinities of five flavanoids with 4'-OH and 7-OH positioned substituents (Hesperitin, Steppogenin, Genistein, Butin, and Homoeriodictyol) against the KAS III enzymes of two highly resistant bacterial species, S. aureus and E. coli. When docking the flavonoids with the crystal structure of E. coli KAS III, Butin, Homoeriodictyol, Hesperetin and Steppogenin are shown to have the most favorable docking scores of -8.4, -8.5, and -8.7 respectively. Hydrogen bonding between the flavonoids and active site amino acids Arg-36 and Asn-247 were most common among successfully docked flavonoids, as indicated by Steppogenin, Butin, and Hesperitin. When docked with saKAS III, the docking scores of Butin, Hesperitin, Homoeriodictyol, and Steppogenin were very similar to that of the control ligand, as well as showing suitable hydrogen bonding combinations with Cys-112, Phe-298, Ser-152, and Asn-268. This suggests that these compounds may have similar inhibitory effects to the control ligand. As a result, Butin, Hesperetin, and Steppogenin may have potential for enzyme inhibition in in vitro studies The presence of hydrogen bond formation in the active site indicates potential inhibition of the enzyme, suggesting need for further studies to assess the inhibition of beta-keto-acyl carrier synthase III. Understanding the interactions between possible inhibitors with the enzyme may improve drug design and development for treating bacterial infections.