Identification of natural DHFR inhibitors in MRSA strains: Structure-based drug design study

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) is also known as a superbug because of its resistance against multiple antibiotics. It is an opportunistic pathogen that targets immune-compromised people with higher fatality rate and is difficult to treat. This study targets DHFR protein of Staphylococcus aureus (saDHFR), which is a crucial enzyme for its survival and is involved in the synthesis of 5,6,7,8-tetrahydrofolate, an essential cofactor involved in multiple metabolic pathways. In this study, a library of compounds with antimicrobial activity produced by Streptomyces sp. was screened for inhibitory activity towards saDHFR. Through structure-based drug design approach, the compounds showing higher affinity towards saDHFR active site and lower affinity towards human DHFR (huDHFR) were selected, which were further screened down based on their ADMET properties. Two compounds, BRN-1354521 and CHEMBL487191 were identified as the lead molecules exhibiting higher affinity towards saDHFR validated by MD simulations and binding energy calculations using MMGBSA method. This study could lay the foundation for the discovery of novel inhibitors of saDHFR with high therapeutic index to tackle the emerging resistance in Staphylococcus aureus.

Keywords

• MRSA
• DHFR
• Streptomyces