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In Silico Screening of Natural Metabolites as Inhibitors of Biosynthesis and Transport of Enterobactin

J. C. Rosy,Haribalaganesh Ravinarayanan,Palaniappan Gokila,Thirumudikari,Navamuthumani,Shakti Chandra Vadhana Marimuthu,Selvaraj Kunjiappan,K. Sundar

Published 2022 in Biointerface Research in Applied Chemistry

ABSTRACT

As antibiotic resistance is becoming a more serious issue, eliminating essential nutrients from the microenvironment of pathogens, thereby diminishing their growth, would be an effective alternative to widely used antibiotics. Inhibition of iron sequestration in bacteria is one of the alternative antibacterial strategies. As bacteria use siderophores, small molecules that chelate iron from host proteins for iron sequestration, inhibition of siderophore biosynthesis and transport would be a promising way of finding an alternative to the antibiotics. The objective of the current work was to screen for natural metabolites as potential binders of selected drug targets involved in iron acquisition in E. coli. Isochorismate synthase (ICS), an enzyme involved in siderophore biosynthesis, enterobactin, and a membrane protein FepA transports enterobactin-Fe complex into bacterial cells, were chosen as drug targets. Forty-three marine metabolites and 87 plant metabolites were screened in silico, as inhibitors for the selected drug targets. Three marine metabolites viz. Plakorstatin B (-8.76) laurenditerpenol (-8.44), isogranulatimide (-8.39) and, and two plant metabolites: quercetin (-7.97) from Withania somnifera and vomifoliol (-7.96) from Morinda citrifolia were the top-binders for ICS, and further analysis indicated that these compounds interact with the same amino acids that are interacting with the natural ligand of ICS. Withanolide D (-12.61) from W. somnifera, rubiadin (-12.25), and daucosterol (-11.87) from M. citrifolia, and two marine metabolites: bistramide A (-11.8) and isogeoditin A (-11.56) were found to be the top-binders for FepA. These compounds could act as lead molecules for the design and development of effective siderophore inhibitors, thereby controlling the growth of microbial pathogens.

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