Structure-Based Discovery of Inhibitors Against MurE in Methicillin-Resistant Staphylococcus Aureus

Abstract

The rise of superbugs is a serious public health concern. It is estimated to kill around 10 million people a year by 2050 and will overtake cancer as the number one cause of death worldwide. One of the most prevalent drug-resistant pathogen is Methicillin-resistant Staphylococcus aureus (MRSA). Intense efforts have been devoted to the discovery and development of anti-MRSA drug. Muramyl ligase E (MurE), an enzyme involved in the peptidoglycan biosynthesis of the bacterial cell wall, is a highly druggable target in MRSA. In this study, virtual screening of approved and experimental drugs in the Drug Bank database was performed based on a pharmacophore derived from the structure of MurE. Molecular docking was subsequently done with the top hits. The top hits and their derivatives were further evaluated for their predicted pharmacokinetics properties. This drug repurposing effort has identified four experimental drugs that are predicted to bind more strongly to MurE than the drug Fosfomycin. One of the top hits, DB01758, exhibited all the characteristics of a good drug candidate, albeit it is likely to be non-biodegradable.