A structure activity relationship study of 3,4′-dimethoxyflavone for ArlRS inhibition in Staphylococcus aureus

Abstract

Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are difficult to treat due to their resistance to many β-lactam antibiotics, and their highly coordinated excretion of virulence factors. One way in which MRSA accomplishes this is by responding to environmental stimuli using two-component systems (TCS). The ArlRS TCS has been identified as having a key role in regulating virulence in both systemic and local infections caused by S. aureus. We recently disclosed 3,4′-dimethoxyflavone as a selective ArlRS inhibitor. In this study we explore the structure–activity relationship (SAR) of the flavone scaffold for ArlRS inhibition and identify several compounds with increased activity compared to the parent. Additionally, we identify a compound that suppresses oxacillin resistance in MRSA, and begin to probe the mechanism of action behind this activity.